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Competing Interests: ID-J declares consulting fees from AstraZeneca, Bayer, BostonGene, Bristol Myers Squibb, Catalyst, Eli Lilly, Epi-Q, Genentech, Gilead, Janssen, Merus, Novocure, Pfizer, Roche, Sanofi-Genzyme, Syros, ThermoFisher Scientific, and Xcovery; and honoraria from Foundation Medicine, Creative Education Concepts, OncLive, ASCO Post, DAVA Oncology, Medscape, Research to Practice, Total Health, Aptitude Health, American Lung Association, PeerVIew, and Curio. MGZ declares consulting fees from Roche Diagnostics, Curis, and Ikena; honoraria from Physicians' Education Resource and Medscape; and research funding to Memorial Sloan Kettering Cancer Center from Vivace, MedImmune, Precog, GSK, Epizyme, Polaris, Sellas Life Sciences, Bristol Myers Squibb, Millenium, Curis, and Atara. MGZ also serves as Chair of the Board of Directors of the Mesothelioma Applied Research Foundation, an uncompensated position.

Introduction: The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK -positive or ALK -negative advanced NSCLC, respectively., Methods: Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1., Results: In the avelumab plus lorlatinib group ( ALK -positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group ( ALK -negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%-70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%-57%) with avelumab plus crizotinib (all partial responses)., Conclusions: Avelumab plus lorlatinib treatment in ALK -positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK -negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group., Clinicaltrialsgov Identifier: NCT02584634., Competing Interests: Dr. Solomon reports providing a consulting or advisory role for Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Cancer Council of Victoria, D3 Bio, Janssen, Lilly, the healthcare business of Merck KGaA, Darmstadt, Germany, Pfizer, Roche/Genentech, Takeda, and Thoracic Oncology Group of Australasia; has provided speaker services for Amgen, AstraZeneca, Pfizer, and Roche/Genentech; and has received institutional research funding from 10.13039/100017239BeiGene, 10.13039/100002491Bristol Myers Squibb, 10.13039/100020536Lilly, 10.13039/100004336Novartis, Nuvalent, 10.13039/100004319Pfizer, 10.13039/100004337Roche/10.13039/100004328Genentech, and 10.13039/100004339Sanofi. Prof. Dagogo-Jack reports providing a consulting or advisory role for AstraZeneca, Bayer, Boehringer Ingelheim, BostonGene, Catalyst Pharmaceuticals, Genentech, Janssen, Novocure, Pfizer, Sanofi, Syros Pharmaceuticals, and Xcovery; has received travel, accommodations, or expenses from Array BioPharma, Creative Educational Concepts, DAVA Oncology, Medscape, OncLive/MJH Life Sciences, Pfizer, The ASCO Post, and Total Health Conferencing; and has received institutional research funding from 10.13039/100007174Array BioPharma, 10.13039/100017658Calithera Biosciences, Genentech, Pfizer, 10.13039/100004336Novartis, and Vivace Therapeutics. Prof. Lee reports providing a consulting or advisory role for AstraZeneca/MedImmune, Bristol Myers Squibb, and Novartis; has received honoraria from AstraZeneca/MedImmune, the healthcare business of Merck KGaA, Darmstadt, Germany, and Roche; and has received travel, accommodations, or expenses from Novartis. Prof. Boyer reports providing a consulting or advisory role for AstraZeneca/MedImmune, Bristol Myers Squibb, and Merck & Co., Kenilworth, NJ; has received institutional research funding from 10.13039/100002429Amgen, 10.13039/100019621Ascentage Pharma, 10.13039/100004325AstraZeneca, 10.13039/100017239BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, 10.13039/100004334Merck & Co., Kenilworth, NJ, OncoMed, 10.13039/100012742Peregrine Pharmaceuticals, Pfizer, and Roche/Genentech; and has received travel, accommodations, or expenses from Boehringer Ingelheim, Bristol Myers Squibb, Merck & Co., Kenilworth, NJ, and Roche/Genentech. Prof. Ramalingam reports providing a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly/ImClone, Roche/Genentech, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Carcereny has no relationships to disclose. Prof. Felip reports providing a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, GlaxoSmithKline, Janssen, Merck & Co., Kenilworth, NJ, Novartis, Pfizer, Puma Biotechnology, Roche, Sanofi, Genzyme, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany; has provided speaker services for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Medscape, Merck & Co., Kenilworth, NJ, Novartis, PeerVoice, Pfizer, Prime Oncology, Roche, Springer, Takeda, touchIME, and CME Outfitters; has received research funding from grant for Oncology Innovation, Fundación Merck Salud, Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany; and is an independent member of the board of Grifol. Dr. Han reports providing a consulting or advisory role for Merck & Co., Kenilworth, NJ; has received honoraria from Novartis; and has received institutional research funding from Roche. Dr. Hida has received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Clovis Oncology, Kissei Pharmaceutical, Lilly, Merck & Co., Kenilworth, NJ, Novartis, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical; and has received institutional research funding from 10.13039/100006483AbbVie, 10.13039/501100004948Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Clovis Oncology Daiichi Sankyo, 10.13039/501100002975Dainippon Sumitomo Pharma, 10.13039/501100003769Eisai, 10.13039/100014584Ignyta, 10.13039/100016288Kissei Pharmaceutical, 10.13039/501100004095Kyowa Hakko Kirin, 10.13039/100004334Merck & Co., Kenilworth, NJ, Novartis, Ono Pharmaceutical, Pfizer, Servier, 10.13039/100009954Taiho Pharmaceutical, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Hughes reports providing a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Pfizer, Merck & Co., Kenilworth, NJ, and Roche. Dr. Kim has no relationships to disclose. Dr. Nishio has received lecture fees from Chugai Pharmaceutical, Pfizer, Novartis, and Takeda. Dr. Seto has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Kissei Pharmaceutical, Kyowa Hakko Kirin, Lilly Japan, Merck & Co., Kenilworth, NJ, Nippon Kayaku, Ono Pharmaceutical, Pfizer, Roche Singapore, Taiho Pharmaceutical, Takeda, and Yakult Honsha; and has received institutional research funding from Astellas Pharma, AstraZeneca, 10.13039/100015731Bayer Yakuhin, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Eisai, Kissei Pharmaceutical, Lilly, Merck & Co., Kenilworth, NJ, Novartis, Pfizer, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Okamoto has received honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Johnson & Johnson, Merck & Co., Kenilworth, NJ, Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical; and has received institutional research funding from AnHeart Therapeutics, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Lilly, KM Biologics, the healthcare business of Merck KGaA, Darmstadt, Germany, Merck & Co., Kenilworth, NJ, Boehringer Ingelheim, Nippon Kayaku, Novartis, Pfizer, and Taiho Pharmaceutical. Dr. Zhang is an employee of Pfizer and owns stock and has other ownership interests in Pfizer. Dr. Martini is an employee of Pfizer and owns stock and has other ownership interests in Pfizer. Dr. Wang was an employee of Pfizer at the time this study was conducted. Dr. De Beukelaer was an employee of Pfizer at the time this study was conducted and owns stock and has other ownership interests in Pfizer. Dr. Bauer reports providing a consulting or advisory role for AstraZeneca, Bayer, Lilly, and Pfizer; has provided speaker services for Bayer, Bristol Myers Squibb, Lilly, and Pfizer; and has received institutional research funding from AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, and Pfizer., (© 2024 by the International Association for the Study of Lung Cancer.)

What Is This Summary About?: This is a summary of the results of a study called PHAROS. This study looked at combination treatment with encorafenib (BRAFTOVI ® ) and binimetinib (MEKTOVI ® ). This combination of medicines was studied in people with metastatic non-small-cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer. Metastatic means that the cancer has spread to other parts of the body. All people in this study had a type of NSCLC that has a change in a gene called BRAF termed a BRAF V600E mutation. A gene is a part of the DNA that has instructions for making things that your body needs to work, and the BRAF V600E mutation contributes to the growth of the lung cancer., What Were the Results?: In this study, 98 people with BRAF V600E-mutant metastatic NSCLC were treated with the combination of encorafenib and binimetinib (called encorafenib plus binimetinib in this summary). Before starting the study, 59 people had not received any treatment for their metastatic NSCLC, and 39 people had received previous anticancer treatment. At the time of this analysis, 44 (75%) out of 59 people who did not receive any treatment before taking encorafenib plus binimetinib had their tumors shrink or disappear. Eighteen (46%) out of 39 people who had received treatment before starting encorafenib plus binimetinib also had their tumors shrink or disappear. The most common side effects of encorafenib plus binimetinib were nausea, diarrhea, fatigue, and vomiting., What Do the Results Mean?: These results support the use of encorafenib plus binimetinib combination treatment as a new treatment option in people with BRAF V600E-mutant metastatic NSCLC. The side effects of encorafenib plus binimetinib in this study were similar to the side effects seen with encorafenib plus binimetinib in people with a type of skin cancer called metastatic melanoma.

Objectives: MET amplification is a common mechanism of resistance to second- and third-generation anaplastic lymphoma kinase (ALK) inhibitors. In case series of MET-amplified ALK-rearranged (ALK + ) lung cancer, durability of responses to combinations targeting ALK and MET is variable, suggesting heterogeneity across tumors. However, little is known about the molecular composition of this subset of ALK-rearranged (ALK + ) NSCLC., Materials and Methods: We queried tissue and plasma databases to compile a group of > 50 specimens with ALK rearrangements and concurrent MET amplification. Fluorescence in-situ hybridization (FISH) and next-generation sequencing (NGS) were utilized to quantify the range of MET copies and describe the global molecular landscape of co-altered genes., Results: By FISH, high-level amplification (overall MET/centromere 7 probe ratio ≥ 5) was detected in 75 % of MET-amplified ALK + NSCLC tissue specimens. Intralesional heterogeneity of MET copies was observed, with high-level amplification identified even in cells from tumors with overall low-level MET amplification. Analysis of 48 MET-amplified ALK + NSCLC plasma specimens suggested that high-level amplification is rarely (17 %) detected in plasma. In both tissue and plasma, EML4-ALK variant 1 was the predominant variant (51 %) identified in MET-amplified specimens. ALK kinase domain mutations were only present in a minority of MET-amplified ALK + NSCLCs. MET-amplified ALK + NSCLC plasma specimens were enriched for TP53 mutations (81 % vs 45 %, p = 0.002), EGFR amplification (17 % vs 4 %, p < 0.001), and MYC amplification (21 % vs 3 %, p < 0.001) compared to ALK + NSCLC specimens lacking MET amplification., Conclusions: MET-amplified, ALK + NSCLC often presents with high-level and heterogeneous amplification in tissue, seldom overlaps with ALK mutations, and frequently co-occurs with alterations associated with aggressive tumor biology., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [IDJ has received honoraria from Foundation Medicine, Creative Education Concepts, OncLive, ASCO Post, DAVA Oncology, Medscape, PeerView, Research to Practice, Total Health, Aptitude Health, American Lung Association; consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, BostonGene, Bristol Myers Squibb, Catalyst, Genentech, Gilead, Janssen, Merus, Novocure, Pfizer, Roche, Sanofi-Genzyme, Syros, ThermoFisher Scientific, and Xcovery, research support from Array, Genentech, Novartis, Pfizer, and Guardant Health; and travel support from Array and Pfizer. LAK is an employee and shareholder of Guardant Health. JKL has no disclosures to report]., (Copyright © 2023. Published by Elsevier B.V.)

Pleural mesothelioma is an aggressive disease that is enriched for inactivating alterations in tumor suppressor genes. Systemic therapeutic strategies for pleural mesothelioma generally involve chemotherapies and immunotherapies that are chosen without consideration of the tumor's molecular profile. As this generalized approach to treatment rarely yields durable responses, alternative therapeutic regimens are urgently indicated. Preclinical studies have identified synthetic lethal protein and metabolic interactions, recurrently overexpressed proteins, and frequent pathway perturbations that may be therapeutically exploited in mesothelioma. This review discusses the mechanism of action of emerging investigational therapies and summarizes findings from phase I-II clinical trials exploring selective, biomarker-driven therapeutic strategies for mesothelioma, with a focus on five common targets. Finally, using lessons learned from these clinical trials, imperatives for successful implementation of targeted therapy in mesothelioma are discussed.

Purpose: Targeted therapy yields superior outcomes relative to genotype-agnostic therapy for patients with epidermal growth factor receptor ( EGFR )-mutant lung cancer. Workflows that facilitate timely detection of EGFR mutations and early dispensation of osimertinib can improve management of this disease., Methods: We developed an Integrated Radiology, Pathology, and Pharmacy Program to minimize delays in initiating osimertinib. The intervention consisted of parallel workflows coupling interventional radiology, surgical pathology, and analysis of nucleic acids from frozen tissue with early pharmacy engagement. We compared time to EGFR testing results and time to treatment for participating patients with those of historical cohorts., Results: Between January 2020 and December 2021, 222 patients participated in the intervention. The median turnaround time from biopsy to EGFR results was 1 workday. Forty-nine (22%) tumors harbored EGFR exon 19 deletions or EGFR L858R. Thirty-one (63%) patients were prescribed osimertinib via the intervention. The median interval between osimertinib prescription and osimertinib dispensation was 3 days; dispensation occurred within 48 hours for 42% of patients. The median interval between biopsy and osimertinib dispensation was 5 days. Three patients received osimertinib within 24 hours of EGFR results. Compared with patients with EGFR- mutant non-small-cell lung cancer who were diagnosed through routine workflows, the intervention led to a significant reduction in median time between biopsy and EGFR results (1 v 7 days; P < .01) and median time to treatment initiation (5 v 23 days; P < .01)., Conclusion: Combining radiology and pathology workflows with early parallel pharmacy engagement leads to a significant reduction in time to initiating osimertinib. Multidisciplinary integration programs are essential to maximize clinical utility of rapid testing.

Introduction: Guidelines recommend obtaining a computed tomography scan of the chest for the staging of pleural mesothelioma and for assessing response to treatment. Consensus is lacking regarding the necessity of serial imaging of distant extrathoracic sites. In this study, we determined the prevalence of extrathoracic metastases in patients with pleural mesothelioma., Methods: We conducted a retrospective review of patients with pleural mesothelioma treated at Massachusetts General Hospital between 1999 and 2022 who were referred for extrathoracic imaging during their disease course. Imaging reports were reviewed to determine sites of metastasis and calculate the time to development of extrathoracic metastasis. Overall survival and prevalence of extrathoracic metastasis were compared for patients with epithelioid versus nonepithelioid mesothelioma., Results: The study included 148 patients, 69 (47%) of whom had undergone cytoreductive surgery. Histologic types included epithelioid (n = 82, 55%), biphasic (n = 49, 33%), and sarcomatoid (n = 10, 7%) mesothelioma. The median overall survival for the cohort was 24.0 months, specifically 34.7 months and 16.7 months for patients with epithelioid and nonepithelioid tumors, respectively ( p < 0.001). There were 65 (44%) patients who developed extrathoracic metastases, with a median time to extrathoracic metastasis of 11.5 months. The most common sites of involvement were extrathoracic nodes (22%), peritoneum (20%), bone (11%), and liver (11%). Of the 76 patients referred for brain imaging, seven (9%) had brain metastases. The frequency of extrathoracic metastasis was identical for epithelioid and nonepithelioid mesothelioma (44%). Overall survival was shorter for patients who developed extrathoracic metastases (hazard ratio 5.9, p < 0.001)., Conclusions: Patients with pleural mesothelioma often develop extrathoracic metastases, providing a rationale for routinely obtaining imaging that encompasses sites outside of the thoracic cavity., (© 2023 The Authors.)

Purpose: The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with BRAF V600E/K -mutant metastatic melanoma. We evaluated the efficacy and safety of encorafenib plus binimetinib in patients with BRAF V600E -mutant metastatic non-small-cell lung cancer (NSCLC)., Methods: In this ongoing, open-label, single-arm, phase II study, patients with BRAF V600E -mutant metastatic NSCLC received oral encorafenib 450 mg once daily plus binimetinib 45 mg twice daily in 28-day cycles. The primary end point was confirmed objective response rate (ORR) by independent radiology review (IRR). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival, time to response, and safety., Results: At data cutoff, 98 patients (59 treatment-naïve and 39 previously treated) with BRAF V600E -mutant metastatic NSCLC received encorafenib plus binimetinib. Median duration of treatment was 9.2 months with encorafenib and 8.4 months with binimetinib. ORR by IRR was 75% (95% CI, 62 to 85) in treatment-naïve and 46% (95% CI, 30 to 63) in previously treated patients; median DOR was not estimable (NE; 95% CI, 23.1 to NE) and 16.7 months (95% CI, 7.4 to NE), respectively. DCR after 24 weeks was 64% in treatment-naïve and 41% in previously treated patients. Median PFS was NE (95% CI, 15.7 to NE) in treatment-naïve and 9.3 months (95% CI, 6.2 to NE) in previously treated patients. The most frequent treatment-related adverse events (TRAEs) were nausea (50%), diarrhea (43%), and fatigue (32%). TRAEs led to dose reductions in 24 (24%) and permanent discontinuation of encorafenib plus binimetinib in 15 (15%) patients. One grade 5 TRAE of intracranial hemorrhage was reported. Interactive visualization of the data presented in this article is available at the PHAROS dashboard (https://clinical-trials.dimensions.ai/pharos/)., Conclusion: For patients with treatment-naïve and previously treated BRAF V600E -mutant metastatic NSCLC, encorafenib plus binimetinib showed a meaningful clinical benefit with a safety profile consistent with that observed in the approved indication in melanoma.

Introduction: MET amplification is a potentially actionable resistance mechanism in ALK -rearranged (ALK+) lung cancer. Studies describing treatment outcomes of this molecular subgroup are lacking., Methods: We assembled a cohort of patients with ALK+ lung cancer and acquired MET amplification (identified by tissue or plasma) who received regimens targeting both ALK and MET. Efficacy and safety were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 and Common Terminology Criteria for Adverse Events version 4.03, respectively., Results: A total of 12 patients were included in the series. MET amplification was detected after a median of 1.5 (range 1-5) lines of therapy. Four distinct regimens were implemented to address MET amplification: crizotinib (n = 2), lorlatinib plus crizotinib (n = 6), alectinib plus capmatinib (n = 3), and alectinib plus crizotinib (n = 1). Partial responses were observed in five (42%) of 12 patients, including patients who received crizotinib (n = one of two), lorlatinib plus crizotinib (n = three of six), and alectinib plus capmatinib (n = one of three). Primary progression was observed in four patients (33%). Grades 1 to 2 peripheral edema, occurring in seven (58%) patients, was found with both crizotinib and capmatinib. One patient required dose reduction of capmatinib plus alectinib for persistent grade 2 edema. Across the regimens, one patient discontinued therapy for toxicity, specifically neurocognitive toxicity from lorlatinib plus crizotinib. At progression on ALK+ MET therapy, potential resistance mechanisms included MET copy number changes and ALK kinase domain mutations., Conclusions: Combined ALK and MET inhibition is associated with moderate antitumor activity in patients with ALK+ NSCLC with concurrent MET amplification. Prospective studies are indicated to confirm activity and identify individuals most likely to benefit from the treatment., (© 2023 The Authors.)

Introduction: Relapse is common after resection of lung adenocarcinoma (LUAD). Features of the tumor microenvironment (TME) which influence postsurgical survival outcomes are poorly characterized. Here, we analyzed the TME of more than 1500 LUAD specimens to identify the relationship between B-cell infiltration and prognosis., Methods: Whole exome sequencing and bulk RNA sequencing were performed on LUADs and adjacent normal lung tissue. Relapse-free survival and overall survival (OS) were retrospectively correlated with characteristics of the tumor and TME in three data sets., Results: High B-cell content (defined as >10% B cells) was associated with improved OS in both a The Cancer Genome Atlas-resected LUAD data set ( p  = 0.01) and a separate institutional stage II LUAD data set ( p  = 0.04, median not reached versus 89.5 mo). A validation cohort consisting of pooled microarray data representing more than 1400 resected stage I to III LUADs confirmed the association between greater B-cell abundance, specifically higher B-cell expression, and longer postsurgical survival (median OS 90 versus 71 mo, p < 0.01). Relapse-free survival was longer for patients with adenocarcinomas with high B-cell content across data sets, but it did not reach statistical significance. Subcategorization of B-cell subsets indicated that high naive B-cell content was most predictive of survival. There was no correlation between programmed death-ligand 1 expression, lymphoid aggregates, or overall immune infiltrate density and survival outcomes across the cohorts., Conclusions: The growing adjuvant immunotherapy repertoire has increased the urgency for identifying prognostic and predictive biomarkers. Comprehensive profiling of more than 1500 LUADs suggests that high tumor-infiltrating B-cell content is a favorable prognostic marker., (© 2023 The Authors.)

Lung cancer is the leading cause of cancer-related deaths worldwide. Surgery and chemoradiation are the standard of care in early stages of non-small cell lung cancer (NSCLC), while immunotherapy is the standard of care in late-stage NSCLC. The immune composition of the tumor microenvironment (TME) is recognized as an indicator for responsiveness to immunotherapy, although much remains unknown about its role in responsiveness to surgery or chemoradiation. In this pilot study, we characterized the NSCLC TME using mass cytometry (CyTOF) and bulk RNA sequencing (RNA-Seq) with deconvolution of RNA-Seq being performed by Kassandra, a recently published deconvolution tool. Stratification of patients based on the intratumoral abundance of B cells identified that the B-cell rich patient group had increased expression of CXCL13 and greater abundance of PD1 + CD8 T cells. The presence of B cells and PD1 + CD8 T cells correlated positively with the presence of intratumoral tertiary lymphoid structures (TLS). We then assessed the predictive and prognostic utility of these cell types and TLS within publicly available stage 3 and 4 lung adenocarcinoma (LUAD) RNA-Seq datasets. As previously described by others, pre-treatment expression of intratumoral 12-chemokine TLS gene signature is associated with progression free survival (PFS) in patients who receive treatment with immune checkpoint inhibitors (ICI). Notably and unexpectedly pre-treatment percentages of intratumoral B cells are associated with PFS in patients who receive surgery, chemotherapy, or radiation. Further studies to confirm these findings would allow for more effective patient selection for both ICI and non-ICI treatments., (© 2023 The Authors. FASEB BioAdvances published by Wiley Periodicals LLC on behalf of The Federation of American Societies for Experimental Biology.)

Patients with interstitial lung disease (ILD), especially those with pulmonary fibrosis, are at increased risk of developing lung cancer. Management of lung cancer in patients with ILD is particularly challenging. Diagnosis can be complicated by difficulty differentiating lung nodules from areas of focal fibrosis, and percutaneous biopsy approaches confer an increased risk of complications in those with pulmonary fibrosis. Lung cancer treatment in these patients pose several specific considerations. The degree of lung function impairment may preclude lobectomy or surgical resection of any type. Surgical resection can trigger an acute exacerbation of the underlying ILD. The presence of ILD confers an increased risk of pneumonitis with radiotherapy, and many of the systemic therapies also carry an increased risk of pneumonitis in this population. The safety of immunotherapy in the setting of ILD remains to be fully elucidated and concerns remain as to triggering pneumonitis. The purpose of this review is to summarize the evidence regarding consideration for tissue diagnosis, chemotherapy and immunotherapy, radiotherapy, and surgery, in this patient population and discuss emerging areas of research. We also propose a multidisciplinary approach and practical considerations for monitoring for ILD progression during lung cancer treatment., (© The Author(s) 2022. Published by Oxford University Press.)

Introduction: The safety profile of lorlatinib includes neurocognitive adverse events (NAEs). Baseline factors associated with developing NAEs remain poorly characterized., Methods: Records from patients who received lorlatinib through prospective studies at Massachusetts General Hospital (MGH, n = 124) or the phase 1/2 B7461001 (NCT01970865; n = 248) study were reviewed to identify potential associations between comorbidities, baseline medications, and NAEs., Results: Most patients experienced a NAE (MGH: 60%, B7461001: 49%). Cognitive effects occurred in 40% and 29% of patients in the MGH and B7461001 cohorts, respectively. Brain metastases (p = 0.008), brain radiation (p = 0.033), psychiatric illness (p = 0.008), psychiatric medications (p < 0.001), antiepileptics (p < 0.001), and stimulants (p = 0.026) were associated with developing cognitive effects in B7461001. Mood effects occurred in 36% and 23% of patients in the MGH and B7461001 cohorts, respectively. In the MGH cohort, psychiatric illness (p = 0.02) and stimulants (p = 0.01) were associated with developing mood effects whereas brain surgery (p = 0.020), psychiatric medications (p < 0.001), benzodiazepines (p = 0.002), and sedatives (p = 0.034) were associated with developing mood effects in B7461001. Psychotic effects were infrequent (MGH: 3%, B7461001: 9%) and were associated with brain surgery in the MGH cohort (p = 0.001) and age in B7461001 (p = 0.014). Speech effects were observed in 23% and 11% of patients in the MGH and B7461001 cohorts, respectively. Brain radiation (p = 0.012) and antiepileptics (p < 0.001) were associated with speech effects in B7461001. Dose reductions were implemented for 52% and 18% of patients with NAEs in MGH and B7461001 cohorts, respectively, with mitigating effect., Conclusions: Neurocognitive effects from lorlatinib are common. Lorlatinib-related NAEs may be influenced by multiple factors, including brain metastases, brain radiation, psychiatric illness, and use of neurotropic medications., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows., Methods: Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network., Results: Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of "abnormal" results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network., Conclusion: Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology., (© The Author(s) 2022. Published by Oxford University Press.)

Introduction: Co-occurring mutations in KRAS -mutant NSCLC are associated with discrete biological properties and modulate therapeutic susceptibilities. As G12D-specific inhibitors are expected to enter the clinic, we sought to investigate the characteristics and outcomes of patients with KRAS G12D-mutant NSCLC., Methods: This was a retrospective single-institution study. Patients with NSCLC and KRAS G12D mutations detected by the Massachusetts General Hospital SNaPshot next-generation sequencing assay were identified. Clinical and pathologic characteristics were collected by chart review., Results: A total of 107 patients with KRAS G12D-mutant NSCLC were identified. Most patients were former smokers (80, 74.8%) and had tumors with adenocarcinoma pathologic subtype (93, 86.9%). Among 56 patients evaluated for programmed death-ligand 1 expression, tumor proportion score was less than 50% in 43 (76.8%). Concomitant mutations were identified in STK11 (17 of 107, 15.9%), KEAP1 (10 of 58, 17.2%), TP53 (36 of 107, 33.6%), and SMARCA4 (11 of 107, 10.3%). Among 57 patients treated with first-line therapy, patients with STK11 co-mutations had shorter progression-free survival (1.2 mo, 95% confidence interval [CI]: 0.6-2.9 versus 4.1 mo, 95% CI: 2.5-6.0, p  = 0.0235) and overall survival (4.3 mo, 95% CI: 1.2-10.6 versus 17.9 mo, 95% CI: 8.6-31.1, p  = 0.0018) compared with wild type. Patients with KEAP1 co-mutations had shorter overall survival (4.6 mo, 95% CI: 1.2-10.6 versus 17.9 mo, 95% CI: 7.1-30.1, p  = 0.0125) than those without. TP53 co-mutations exerted no influence on survival., Conclusions: Co-occurring mutations were common in patients with KRAS G12D-mutant NSCLC. STK11 and KEAP1 co-mutations were associated with worse clinical outcomes, whereas co-occurring TP53 did not affect survival., (© 2022 The Authors.)

Purpose: Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established., Methods: We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival., Results: A total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors., Conclusion: This meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population., Competing Interests: Benny JohnsonConsulting or Advisory Role: Gritstone Bio, Incyte, Taiho Oncology, InsmedResearch Funding: Bristol Myers Squibb (Inst), Syntrix Biosystems (Inst) Ibiayi Dagogo-JackHonoraria: American Academic Health System, Total Health Conferencing, DAVA Oncology, Creative Educational Concepts, Medscape, ASCO Post, OncLive/MJH Life SciencesConsulting or Advisory Role: Boehringer Ingelheim, AstraZeneca, Xcovery, Catalyst Pharmaceuticals, Pfizer, Syros Pharmaceuticals, Novocure, BostonGene, Bayer, Genentech, Sanofi, JanssenResearch Funding: Pfizer (Inst), Array BioPharma (Inst), Novartis (Inst), Genentech (Inst), Calithera Biosciences (Inst), Vivace Therapeutics (Inst)Travel, Accommodations, Expenses: Pfizer, Array BioPharma Nathaniel J. MyallHonoraria: Patient Power Georg RichtigTravel, Accommodations, Expenses: Ipsen Marco GerlingerStock and Other Ownership Interests: VertexResearch Funding: Bristol Myers Squibb, Merck KGaA, Roche/Genentech Eiji ShinozakiHonoraria: Yakult Honsha, Merck Serono, Chugai Pharma, Takeda, Sanofi, Lilly, Taiho Pharmaceutical, Daiichi Sankyo/UCB Japan Takayuki YoshinoHonoraria: Chugai Pharma, Merck, Bayer Yakuhin, Ono Pharmaceutical, MSD K.K.Research Funding: MSD (Inst), Daiichi Sankyo Company, Limited (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Amgen (Inst), Sanofi (Inst), Pfizer (Inst), Genomedia (Inst), Sysmex (Inst), Nippon Boehringer Ingelheim (Inst), Chugai Pharma (Inst) Daisuke KotaniHonoraria: Takeda, Chugai Pharma, Lilly Japan, Merck Serono, Sysmex, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD, Daiichi Sankyo/UCB JapanResearch Funding: Ono Pharmaceutical (Inst), MSD (Inst), Novartis (Inst), Janssen (Inst), IQvia (Inst), Syneos Health (Inst), CMIC (Inst) Jason R. FangusaroHonoraria: AstraZeneca, Pyramid BiosciencesConsulting or Advisory Role: Celgene, AstraZeneca Oliver GautschiConsulting or Advisory Role: Amgen (Inst), Lilly (Inst)Other Relationship: Bayer (Inst), Pfizer (Inst), Roche (Inst), Merck, Lilly Julien MazieresConsulting or Advisory Role: Novartis, Roche/Genentech, Pfizer, Bristol Myers Squibb, Lilly/ImClone, MSD, AstraZeneca, Pierre Fabre, Blueprint Medicines, Hengrui TherapeuticsResearch Funding: Roche (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Pierre Fabre (Inst)Travel, Accommodations, Expenses: Pfizer, Roche, Bristol Myers Squibb Jeffrey A. SosmanHonoraria: Jazz Pharmaceuticals, Apexian Pharmaceuticals, Iovance BiotherapeuticsConsulting or Advisory Role: Apexigen, Jazz Pharmaceuticals, Iovance Biotherapeutics Scott KopetzThis author is a member of the JCO Precision Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Stock and Other Ownership Interests: MolecularMatch, Lutris, Iylon, Frontier MedicinesConsulting or Advisory Role: Genentech, EMD Serono, Merck, Holy Stone Healthcare, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, Redx Pharma, Ipsen, Daiichi Sankyo, Natera, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, GlaxoSmithKline, Jazz Pharmaceuticals, Iylon, Xilis, AbbVie, Amal Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotech, Bicara Therapeutics, Endeavor BioMedicines, Numab, Johnson & Johnson/Janssen, Genomic Health, Frontier Medicines, Replimune, Taiho PharmaceuticalResearch Funding: Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, Daiichi Sankyo Vivek SubbiahConsulting or Advisory Role: MedImmune, Helsinn Therapeutics, Loxo, R-Pharm, QED TherapeuticsResearch Funding: Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech/Roche (Inst), Berg Pharma (Inst), Bayer (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Inst), Amgen (Inst), AbbVie (Inst), Multivir (Inst), Blueprint Medicines (Inst), LOXO (Inst), Vegenics (Inst), Takeda (Inst), Alfasigma (Inst), Agensys (Inst), Idera (Inst), Boston Biomedical (Inst), Inhibrx (Inst), Exelixis (Inst), Turning Point Therapeutics (Inst)Travel, Accommodations, Expenses: PharmaMar, Bayer, Novartis, Helsinn TherapeuticsOther Relationship: Medscape Michael A. DaviesConsulting or Advisory Role: Genentech/Roche, Novartis, Bristol Myers Squibb, NanoString Technologies, Array BioPharma, Apexigen, Pfizer, Eisai, ABM, Iovance BiotherapeuticsResearch Funding: GlaxoSmithKline (Inst), Genentech/Roche (Inst), AstraZeneca (Inst), Merck (Inst), Oncothyreon (Inst), Myriad Genetics (Inst), Sanofi (Inst), Pfizer (Inst), ABM (Inst), LEAD (Inst) Anna L. GrooverEmployment: BioMed Valley Discoveries Ryan J. SullivanConsulting or Advisory Role: Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, Bristol Myers SquibbResearch Funding: Amgen (Inst), Lilly (Inst), BioMed Valley Discoveries (Inst), Merck (Inst), Deciphera (Inst), Roche/Genentech (Inst), Moderna Therapeutics (Inst), Sanofi (Inst), Aeglea Biotherapeutics (Inst), Asana Biosciences (Inst), Viralytics (Inst), Compugen (Inst), Neon Therapeutics (Inst), Pfizer (Inst), BeiGene (Inst), Rubius Therapeutics (Inst), Strategia (Inst) Keith T. FlahertyStock and Other Ownership Interests: Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Apricity Health, Oncoceutics, FOGPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics, Vibliome Therapeutics, Transcode Therapeutics, Soley Therapeutics, Nextech InvestConsulting or Advisory Role: Novartis, Lilly, Oncoceutics, Tvardi Therapeutics, Takeda, Debiopharm Group, OmRx Douglas B. JohnsonConsulting or Advisory Role: Bristol Myers Squibb, Merck, Novartis, Iovance Biotherapeutics, Catalyst Pharmaceuticals, Oncosec, Pfizer, Mosaic ImmunoEngineering, Targovax, MallinckrodtResearch Funding: Incyte, Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Intellectual property and patents pending surrounding use of MHC-II and response to immune therapy David W. CesconConsulting or Advisory Role: Pfizer, AstraZeneca, Novartis, GlaxoSmithKline, Merck, Roche/Genentech, Exact Sciences, Gilead Sciences, EisaiResearch Funding: Merck (Inst), Roche/Genentech (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), Inivata (Inst), AstraZeneca (Inst), Gilead Sciences (Inst)Patents, Royalties, Other Intellectual Property: Patent (US62/675,228) for methods of treating cancers characterized by a high expression level of spindle and kinetochore-associated complex subunit 3 (ska3) geneUncompensated Relationships: Inivata Anna SpreaficoHonoraria: Bristol Myers Squibb, Medison & ImmunocoreConsulting or Advisory Role: Novartis, Merck, Bristol Myers Squibb, Oncorus, Medison & ImmunocoreResearch Funding: Bristol Myers Squibb, Novartis, Merck, Symphogen, AstraZeneca/MedImmune, Bayer, Surface Oncology, Janssen Oncology, Northern Biologics, Replimune, Roche, Alkermes, Array BioPharma, GlaxoSmithKline, Treadwell Therapeutics (Inst), Amgen (Inst)Travel, Accommodations, Expenses: Merck, Bristol Myers Squibb, Idera, Bayer, Janssen Oncology, Roche George ZogopoulosPatents, Royalties, Other Intellectual Property: TC-PTP inhibitors as APC activators for immunotherapyTravel, Accommodations, Expenses: Baxalta April A.N. RoseEmployment: Merck (I)Stock and Other Ownership Interests: Merck (I)Consulting or Advisory Role: PfizerNo other potential conflicts of interest were reported.

Introduction: The central nervous system (CNS) is a common site of progression among patients with ROS1 -rearranged lung cancer receiving crizotinib. We conducted a phase 2 study to evaluate the intracranial efficacy of lorlatinib in patients with ROS1 -rearranged lung cancer who developed CNS-only progression on crizotinib., Methods: Patients with metastatic ROS1 -rearranged lung cancer with CNS-only progression on crizotinib received lorlatinib 100 mg daily. The primary end point was intracranial disease control rate at 12 weeks per modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included intracranial and extracranial progression-free survival, intracranial objective response rate, and safety/tolerability., Results: A total of 16 patients were enrolled between November 2016 and January 2019. Nine patients (56%) had received prior CNS radiation, with a median of 10.9 months between radiation and lorlatinib. At 12 weeks, the intracranial disease control rate was 100% and intracranial objective response rate was 87%. While on study, the complee intracranial response rate was 60%. With median follow-up of 22 months, seven patients experienced disease progression, including five patients with CNS relapse. The median intracranial and extracranial progression-free survivals were 38.8 months (95% confidence interval: 16.9-not reported) and 41.1 months (95% confidence interval: 17.6-not reported), respectively. Molecular analysis of plasma or tissue from patients with extracranial progression on lorlatinib revealed ROS1 G2032R (n = 1), ROS1 L2086F (n = 1), and CCDC6-RET fusion plus ROS1 G2032R (n = 1). The safety profile of lorlatinib was consistent with prior studies. There were 11 patients (69%) who required dose reduction, including one patient who discontinued treatment for grade 3 edema. No grade greater than or equal to 4 adverse events were observed., Conclusions: Lorlatinib induced durable intracranial responses in patients with ROS1 -rearranged NSCLC and prior isolated CNS progression on crizotinib., (© 2022 The Authors.)

Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Mesothelioma is an aggressive malignancy with heterogeneous outcomes that are partly driven by the differential efficacy of existing therapies across histologic types and sites of origin. Large-scale molecular analysis of mesothelioma and its subtypes has the potential to inform future therapeutic strategies., Materials and Methods: We analyzed 1,294 mesotheliomas {980 pleural (malignant pleural mesothelioma [MPM]) and 314 peritoneal (malignant peritoneal mesothelioma [MPeM])} using next-generation sequencing, determined programmed death ligand-1 (PD-L1) expression and histology in a subset of cases, and assessed MTAP /CDKN2A copy-number status by fluorescence in situ hybridization and T-cell infiltration in an independent cohort., Results: The molecular landscape of MPM was characterized by inactivating alterations in CDKN2A (49%), BAP1 (44%), CDKN2B (42%), MTAP (34%), and NF2 (33%). Compared with epithelioid MPM, nonepithelioid (ie, biphasic and sarcomatoid) MPM had identical tumor mutational burden (median 1.25 mut/Mb, P = .63), more commonly expressed PD-L1 (74% v 51%, P = .02), and was more likely to harbor MTAP , CDKN2A , and CDKN2B copy loss ( P < .05). Fluorescence in situ hybridization confirmed that homozygous MTAP loss was enriched in nonepithelioid MPM. Relative to MPM, MPeM had comparable tumor mutational burden and PD-L1 expression. The molecular profile of MPeM was similar to MPM, with the distinction that PBRM1 alterations occurred at higher frequency (16% v 7%, P < .01). ALK rearrangements were only observed in MPeM., Conclusion: Regardless of histology and location, the molecular landscape of mesothelioma primarily consists of inactivating alterations in tumor suppressor genes, with enrichment of certain alterations in distinct subsets (eg, MTAP loss in nonepithelioid tumors). Given the limited efficacy of current therapies for this disease, novel approaches targeting recurring alterations should be explored., Competing Interests: Ibiayi Dagogo-JackHonoraria: American Academic Health System, Total Health Conferencing, DAVA Oncology, Creative Educational Concepts, Medscape, ASCO Post, OncLive/MJH Life SciencesConsulting or Advisory Role: Boehringer Ingelheim, AstraZeneca, Xcovery, Catalyst Pharmaceuticals, Pfizer, Syros Pharmaceuticals, Novocure, BostonGene, Bayer, Genentech, Sanofi, JanssenResearch Funding: Pfizer (Inst), Array BioPharma (Inst), Novartis (Inst), Genentech (Inst), Calithera Biosciences (Inst), Vivace Therapeutics (Inst)Travel, Accommodations, Expenses: Pfizer, Array BioPharma Russell W. MadisonEmployment: Foundation MedicineStock and Other Ownership Interests: Roche Kuei-Ting ChenEmployment: Foundation MedicineStock and Other Ownership Interests: Roche Julia F. HopkinsEmployment: Foundation MedicineStock and Other Ownership Interests: Roche Alexa B. SchrockEmployment: Foundation MedicineStock and Other Ownership Interests: Foundation Medicine, Roche Lauren L. RitterhouseHonoraria: Merck, AstraZeneca, Genzyme, EMD SeronoConsulting or Advisory Role: Amgen Keith A. WhartonEmployment: UltivueStock and Other Ownership Interests: Danaher, Novartis Mari Mino-KenudsonHonoraria: BMS, SanofiConsulting or Advisory Role: H3 Biomedicine, AstraZeneca/MedImmuneResearch Funding: NovartisPatents, Royalties, Other Intellectual Property: Elsevier Natalie DanzigerEmployment: Foundation MedicineStock and Other Ownership Interests: Roche Yin P. HungPatents, Royalties, Other Intellectual Property: I received royalties for authoring textbook chapters related to surgical pathology/medicine for Elsevier publishing company Douglas A. MataEmployment: Foundation MedicineStock and Other Ownership Interests: RocheConsulting or Advisory Role: Astellas PharmaSpeakers' Bureau: Astellas PharmaPatents, Royalties, Other Intellectual Property: Foundation MedicineTravel, Accommodations, Expenses: Foundation Medicine Jeffrey S. RossEmployment: Foundation MedicineLeadership: Foundation MedicineStock and Other Ownership Interests: Foundation MedicineConsulting or Advisory Role: Celsius Therapeutics, Tango TherapeuticsResearch Funding: Foundation MedicineNo other potential conflicts of interest were reported.

Purpose: The CNS is a recurrent site of progression in anaplastic lymphoma kinase (ALK)-rearranged (ALK+) lung cancer. Lorlatinib is a third-generation ALK inhibitor developed to penetrate the CNS and overcome ALK resistance mutations. We conducted a phase II study to evaluate the intracranial activity of lorlatinib in patients with CNS-only progression on second-generation ALK inhibitors., Methods: Patients with ALK+ lung cancer who had intracranial progression on ≥ 1 ALK inhibitor without measurable extracranial disease received lorlatinib 100 mg once daily. The primary end point was intracranial disease control rate at 12 weeks per modified RECIST v1.1. Secondary end points included intracranial progression-free survival, intracranial objective response rate, and safety/tolerability., Results: Twenty-three patients were enrolled between November 2016 and January 2019. Fifteen (65%) patients had irradiated CNS metastases, with a median of 20.2 months between radiation and lorlatinib. Control of intracranial disease was observed in 21 (95%) evaluable patients at 12 weeks. The intracranial objective response rate was 59% with six complete and seven partial responses. The median intracranial progression-free survival was 24.6 months (95% CI, 20.2 to not reached). With a median follow-up of 16.8 months, nine patients developed disease progression, including four patients with CNS progression. The most common treatment-related adverse events were hypercholesterolemia (96%), hypertriglyceridemia (87%), edema (65%), cognitive effects (52%), and mood effects (43%). Three patients discontinued treatment because of toxicity, including two patients with fatal respiratory events., Conclusion: Lorlatinib induced durable intracranial disease control in patients with CNS-only relapse on second-generation ALK inhibitors, suggesting that tumors with CNS-limited progression on brain-penetrant ALK tyrosine kinase inhibitors remain ALK-dependent., Competing Interests: Ibiayi Dagogo-JackHonoraria: American Academic Health System, Total Health Conferencing, DAVA Oncology, Creative Educational Concepts, Medscape, ASCO Post, OncLive/MJH Life SciencesConsulting or Advisory Role: Boehringer Ingelheim, AstraZeneca, Xcovery, Catalyst Pharmaceuticals, Pfizer, Syros Pharmaceuticals, Novocure, BostonGene, Bayer, Genentech, Sanofi, JanssenResearch Funding: Pfizer (Inst), Array BioPharma (Inst), Novartis (Inst), Genentech (Inst), Calithera Biosciences (Inst), Vivace Therapeutics (Inst)Travel, Accommodations, Expenses: Pfizer, Array BioPharma Geoffrey R. OxnardThis author is a member of the JCO Precision Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Employment: Foundation MedicineStock and Other Ownership Interests: Roche Makenzi EvangelistConsulting or Advisory Role: Takeda, AstraZeneca, Mirati Therapeutics, Regeneron Subba R. DigumarthyHonoraria: SiemensTravel, Accommodations, Expenses: Siemens Healthcare DiagnosticsOther Relationship: provides independent image analysis for hospital-contracted clinical research trials programs for several companies including Merck, Pfizer, Bristol Mayer Squibb, Novartis, Roche, Polaris, Cascadian, AbbVie, Gradalis, Clinical Bay, Zai Laboratories. R (Inst) Jessica J. LinHonoraria: Pfizer, OncLiveConsulting or Advisory Role: C4 Therapeutics, Genentech, Nuvalent Inc, Blueprint Medicines, Turning Point Therapeutics, Bayer, Mirati Therapeutics, Novartis, Elevation OncologyResearch Funding: Hengrui Therapeutics (Inst), Turning Point Therapeutics (Inst), Novartis (Inst), Neon Therapeutics (Inst), Relay Therapeutics (Inst), Elevation Oncology (Inst), Bayer (Inst), Roche (Inst), Linnaeus Therapeutics (Inst), Nuvalent Inc (Inst)Travel, Accommodations, Expenses: Pfizer Justin F. GainorEmployment: Ironwood Pharmaceuticals (I)Stock and Other Ownership Interests: Ironwood Pharmaceuticals (I)Honoraria: Merck, Novartis, Pfizer, Takeda, BeiGeneConsulting or Advisory Role: Genentech, Bristol Myers Squibb, Takeda, Amgen, Merck, Jounce Therapeutics, Blueprint Medicines, Gilead Sciences, Lilly, Moderna Therapeutics, Karyopharm Therapeutics, ITeos Therapeutics, Pfizer, Mirati Therapeutics, Nuvalent Inc, EMD Serono, Silverback Therapeutics, Novartis, BeiGeneResearch Funding: Merck (Inst), Novartis (Inst), Genentech, Bristol Myers Squibb (Inst), Adaptimmune (Inst), AstraZeneca (Inst), Jounce Therapeutics (Inst), Blueprint Medicines (Inst), Moderna Therapeutics (Inst), Tesaro (Inst), Alexo Therapeutics (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/775917 Michael S. RabinStock and Other Ownership Interests: Acuity Bio Rebecca S. HeistHonoraria: Chugai/RocheConsulting or Advisory Role: Novartis, Daiichi Sankyo, EMD Serono/Merck, AbbVieResearch Funding: AbbVie (Inst), Novartis (Inst), Roche (Inst), Incyte (Inst), Celgene (Inst), Mirati Therapeutics (Inst), Peregrine Pharmaceuticals (Inst), Exelixis (Inst), Millennium (Inst), Debiopharm Group (Inst), Corvus Pharmaceuticals (Inst), Daiichi Sankyo (Inst), Agios (Inst), Exelixis (Inst), Pfizer (Inst), Lilly (Inst), Turning Point Therapeutics (Inst) Alice T. ShawEmployment: Novartis Institutes for BioMedical ResearchStock and Other Ownership Interests: Novartis Institutes for BioMedical ResearchNo other potential conflicts of interest were reported.

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results., (© 2021. The Author(s).)