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Purpose: To evaluate safety, tolerability, and anti-tumor response of lete-cel, genetically modified autologous T-cells expressing a T-cell receptor specific for NY-ESO-1/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in human leukocyte antigen HLA-A*02-positive (HLA-A*02:01-, HLA-A*02:05-, and/or HLA-A*02:06-) patients with New York esophageal squamous cell carcinoma 1 (NY-ESO-1)- and/or LAGE-1a-positive non-small cell lung cancer (NSCLC)., Experimental Design: Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multi-arm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent NSCLC., Results: Over 2500 patients were screened for target expression. In the multi-arm study, 738 (45%) of 1638 tested patients were HLA-A*02-positive. NY-ESO-1 and LAGE-1a testing was positive in 12% (62/525) and 4% (15/348) of tested patients, respectively. Forty-one patients positive for HLA-A*02 and antigen expression were screened in the single-arm study. Overall, 43 patients underwent leukapheresis and 18 received lete-cel across studies. Lete-cel demonstrated a manageable safety profile. No fatal treatment-related serious adverse events (AEs) were reported in either study. Cytopenias and cytokine release syndrome were the most common treatment-emergent AEs. Combining pembrolizumab with lete-cel did not appear to increase toxicity over lete-cel alone. Limited anti-tumor activity was observed; one of 18 patients had a durable response persisting for 18 months. Pharmacokinetic data showed similar T-cell expansion in all patients., Conclusions: Extensive HLA-A*02 and antigen expression testing was performed to identify potential participants. Lete-cel was generally well tolerated and had no unexpected AEs. Anti-tumor activity was observed in a limited number of patients.

Competing Interests: Disclosure DF, HW, RV, TE, JGH, JR, VR, BM, AS: None. AW: Consulting fees from AstraZeneca and honoraria from Epic. TM: Speaker Bureau with Genentech. MAS: Grants from Genentech, Spectrum, Cullinan, Lilly, Beigene and AstraZeneca, Consulting fees from BMS, Beigene, Spectrum and Summit, Honoria from Genentech, Lilly, AstraZeneca, Jazz, Janssen, Regeneron, Mirati, participation in DSMB with BMS and Beigene, and leadership role in Elsevier Clinical Pathways. KS: employee of Genentech, stock owner of Roche. LCV: Support for the present manuscript from Genentech, Consulting fees from AstraZeneca, Sanofi, Gilead, Johnson and Johnson, Takeda, EMD Serono, Daiichi Sankyo, Jazz and BMS.

Purpose: The mesothelin-targeting antibody-drug conjugate anetumab ravtansine was evaluated in combination with the programmed cell death-1 (PD-1) inhibitor pembrolizumab based on the common expression of mesothelin and reports of activity in mesothelioma., Patients and Methods: A phase 1 safety run-in of the combination of anetumab ravtansine (6.5 mg/kg iv q3weeks) and pembrolizumab (200 mg, IV q3weeks) was conducted, followed by a phase 2 randomization to the combination or pembrolizumab alone at medical centers across the United States and Canada in the National Cancer Institute's Experimental Therapeutics Clinical Trials Network. Patients with pleural mesothelioma that expressed mesothelin and had previously received platinum-based therapy were eligible., Results: In phase 1 (n = 12) only one dose limiting toxicity was observed and the rules for dose reduction were not met. In phase 2, there was no difference in the confirmed response rates between the combination group (n = 18, 2 partial responses [PR], 11 %) and the pembrolizumab group (n = 17, 1 PR, 6 %; z = -0.5523, p = 0.29116). The median PFS was 12.2 months (95 % CI 5.1-not evaluable [NE]) for the combination, and 3.9 months for pembrolizumab (95 % CI 2.1-NE)(HR=0.55, p = 0.20). Patients with high baseline levels of soluble mesothelin who received anetumab ravtansine had a median PFS of 5 months., Conclusions: The numeric difference in PFS between treatment groups was not statistically significant, likely related to a smaller than planned sample size. High levels of soluble mesothelin should potentially be considered to select against the use of mesothelin-targeting therapies in development that are neutralized by soluble mesothelin., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aaron Mansfield reports receiving support from Genentech and Janssen for manuscript publication; receiving research support to institution from Novartis and Verily; receiving honoraria to institution for participation on advisory boards for AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech, Janssen and Takeda Oncology; serving as steering committee member for Janssen and Johnson & Johnson Global Services; having speaking engagements from Chugai Pharmaceutical Co., Ltd. (Roche); serving as grant reviewer for Rising Tide; having expert think tank participation in TRIPTYCH Health Partners; serving as a moderator for Ideology Health LLC (formerly Nexus Health Media); having CME presentation for Intellisphere LLC (OncLive Summit Series) and Answers in CME; having presentation for Immunocore; serving on the advisory board for Sanofi Genzyme; receiving honoraria to self for CME presentation for Antoni van Leeuwenhoek Kanker Instituut and MJH Life Sciences (OncLive); having presented to the University of Miami International Mesothelioma Symposium; receiving travel support from Roche; serving as nonremunerated director of the Mesothelioma Applied Research Foundation and member of the Friends of Patan Hospital Board of Directors; and receiving study funding and article process charges from Bristol-Myers Squibb. Jose Pacheco reports Advisory Boards with Novartis, AstraZeneca, Takeda, Pfizer, Hengrui Pharmaceuticals, Blueprint Medicines, Silverback Therapeutics, Jazz Pharmaceuticals, Genentech, and Sanofi, and research grant support from CheckMate Pharmaceuticals, Daichii Sankyo, Mirati Therapeutics, Pfizer, Revolution Medicines, Immunomedics, Harpoon Therapeutics. Christian Rolfo has received speaker honoraria from AstraZeneca, Roche and MSD, advisory board honoraria from Inivata, Archer, Boston Pharmaceuticals, MD Serono and Novartis, Bayer, Invitae, Regeneron, Janssen, Bostongene, Novocure, Scientific Advisory Board member of Imagene AI, and institutional research funding from LCRF- Pfizer and NCRF, non-renumerated research support from GuardantHealth and Foundation Medicine. He has non-renumerated leadership roles at the International Society of Liquid Biopsy (ISLB), the International Association for Study of Lung Cancer (IASLC), the European School of Oncology (ESO), and Oncology Latin American Association (OLA). The 3 authors from UNC do not have any COI to report. Aaron Mansfield has been supported by a Mark Foundation ASPIRE Award, Thymic Carcinoma Center Research Award, Department of Defense Concept Award W81XWH-22-1-0021, NCI R21 (CA251923), NCI R33 (CA272271), and NCI U24 (CA283479). Raffit Hassan has received funding from the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (ZIA-BC-010816) and has received funding for conduct of clinical trials via a cooperative research and development agreement between NCI and Bayer AG and TCR(2) Therapeutics., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: JL reports honoraria from Targeted Oncology, Physicians' Education Resource, VJ Oncology, Cancer GRACE, and Community Cancer Education; advisory board participation for AstraZeneca, Amgen, and Astellas; research support to her institution from Erasca, Genentech, Kronos Bio, Novartis, and Revolution Medicines; and personal fees from Erasca, Blueprint Medicines, and Daiichi Sankyo. A patent filed by Memorial Sloan Kettering Cancer Center related to multimodal features to predict response to immunotherapy (PCT/US2023/115872) is pending. LCV has received consulting fees from Takeda, Janssen, Sanofi, Daiichi Sankyo, Jazz Pharmaceuticals, BMS, Gilead, Johnson and Johnson, EMD Serono, and AstraZeneca. The authors acknowledge P A Jänne for helpful discussion about this Comment.

Purpose: This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor]., Experimental Design: Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks)., Results: A total of 159 patients were enrolled in the study and treated with itacitinib (Part 1, n = 49) or parsaclisib (Part 1, n = 83; Part 2, n = 27) plus pembrolizumab. The maximum tolerated/pharmacologically active doses were itacitinib 300 mg once daily and parsaclisib 30 mg once daily. Most common itacitinib treatment-related adverse events (TRAE) were fatigue, nausea, and anemia. Most common parsaclisib TRAEs were fatigue, nausea, diarrhea, and pyrexia in Part 1, and fatigue, maculopapular rash, diarrhea, nausea, and pruritus in Part 2. In patients receiving itacitinib plus pembrolizumab, four (8.2%) achieved a partial response (PR) in Part 1. Among patients receiving parsaclisib plus pembrolizumab, 5 (6.0%) achieved a complete response and 9 (10.8%) a PR in Part 1; 5 of 27 (18.5%) patients in Part 2 achieved a PR., Conclusions: Although combination of itacitinib or parsaclisib with pembrolizumab showed modest clinical activity in this study, the overall response rates observed did not support continued development in patients with solid tumors., Significance: PD-1 blockade combined with targeted therapies have demonstrated encouraging preclinical activity. In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan., Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC., Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible., Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI., Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%])., Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS., Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

Background: Approximately 30-40% of patients with advanced and metastatic non-small cell lung cancer (NSCLC) present with an impaired performance status (PS). There are limited prospective data on the safety and efficacy of durvalumab in these patients., Methods: In this single-arm phase II clinical trial (NCT02879617), patients with previously untreated Stage IIIB/IV NSCLC and ECOG PS of 2 received durvalumab 1500 mg every 28 days until progression or unacceptable toxicity. The primary endpoints were overall survival (OS) and safety determined by grade ≥3 treatment-related adverse events (TRAEs)., Findings: Between April 2017 and March 2021, 50 patients were enrolled, of whom 47 received durvalumab. With a median follow-up of 28 months, median OS was 6 months (95% CI 4-10). TRAEs grade 3 occurred in nine of 47 patients (19%, 95% CI 9%-33%). OS in patients with a PD-L1 TPS of 0, 1-49%, and ≥50% was six months (95% CI 3-15), 11 months (95% CI 4-16), and 11 months (95% CI 0-not reached (NR)), respectively. Health related quality of life (HQRL) assessed at baseline and during therapy demonstrated no statistically significant change over the course of treatment., Interpretation: This study demonstrates that single agent durvalumab is safe and well tolerated in the 1st line treatment of patients with advanced NSCLC and ECOG PS of 2, with an encouraging OS benefit in patients with PD-L1 positive tumors. This trial is amongst the largest prospective studies evaluating durvalumab in the 1st line treatment of advanced stage NSCLC and a PS of 2., Funding: AstraZeneca, NCI P30CA047904., Competing Interests: L.C.V. declares research funding from Janssen, BMS, Merck, Regeneron, GSK, AstraZeneca, BioAtla, Black Diamond Therapeutics, Jazz, Genentech, and Beigene and consulting with compensation with Takeda, Janssen, Intervenn Biosciences, Sanofi, Daiichi Sankyo, Jazz, BMS, and Gilead. D.M. declares consulting with fees from AstraZeneca, Beigene, Cardinal Health, Daiichi Sankyo, Janssen, and Karyopharm. M.A.S. declares research funding from Genentech, Spectrum, Novartis, AstraZeneca, Daiichi-Sankyo, Beigene, Cullinan, Mirati, and Pfizer, speaker bureau fees from Genentech, AstraZeneca, Lilly, Janssen, G1 Therapeutics, BMS, Guardant, Regeneron and participation in steering committee/advisory board membership with Lilly, Beigene, Genentech, Mirati, and Spectrum. J.E.D. declares steering committee/advisory board membership with Janssen, Beigene, Astra Zeneca, Catalyst, Takeda, Oncohost. D.E.G. declares research funding from Astra-Zeneca, BerGenBio, Karyopharm, Novocure, consulting fees from Astra-Zeneca, Catalyst Pharmaceuticals, Daiichi-Sankyo, Elevation Oncology, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, U.S. patent applications 16/487,335, 17/045,482, 63/386,387, 63/382,972, 63/382,257, stock options with Gilead, Medtronic, Walgreens, and Co-founder and Chief Scientific Officer, OncoSeer Diagnostics, LLC. The other authors declare that they have no competing financial interests., (© 2023 The Author(s).)

Background: CREBBP and EP300 mutations occur at a frequency of 15% and 13%, respectively, in small cell lung cancer (SCLC), and preclinical models demonstrated susceptibility to targeting with HDAC inhibitors., Methods: Patients with treatment-naïve extensive-stage SCLC, ECOG ≤2 were enrolled and treated with entinostat orally weekly (4 dose levels, DL) in combination with standard dose carboplatin, etoposide, and atezolizumab. Cohort allocation was determined by Bayesian optimal interval (BOIN) design targeting an MTD with a DLT rate of 20%., Results: Three patients were enrolled and treated at DL1 with entinostat 2 mg. Patients were aged 69-83; 2 male, 1 female; 2 were ECOG 1, and 1 was ECOG 0. The most common adverse events (AEs) were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), and hypocalcemia (2). Two experienced DLTs during cycle 1: (1) grade (Gr) 4 febrile neutropenia, and (1) Gr 5 sepsis. BOIN design required stopping accrual to DL1, and the trial was closed to further accrual. Entinostat and atezolizumab pharmacokinetics were both comparable to historical controls., Conclusion: Addition of entinostat to atezolizumab, carboplatin, and etoposide is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia. Further exploration of entinostat with carboplatin, etoposide, and atezolizumab should not be explored. (ClinicalTrials.gov Identifier: NCT04631029)., (© The Author(s) 2023. Published by Oxford University Press.)

The availability of agents targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint has transformed treatment of advanced and/or metastatic non-small cell lung cancer (NSCLC). However, a substantial proportion of patients treated with these agents do not respond or experience only a brief period of clinical benefit. Even among those whose disease responds, many subsequently experience disease progression. Consequently, novel approaches are needed that enhance antitumor immunity and counter resistance to PD-(L)1 inhibitors, thereby improving and/or prolonging responses and patient outcomes, in both PD-(L)1 inhibitor-sensitive and inhibitor-resistant NSCLC. Mechanisms contributing to sensitivity and/or resistance to PD-(L)1 inhibitors in NSCLC include upregulation of other immune checkpoints and/or the presence of an immunosuppressive tumor microenvironment, which represent potential targets for new therapies. This review explores novel therapeutic regimens under investigation for enhancing responses to PD-(L)1 inhibitors and countering resistance, and summarizes the latest clinical evidence in NSCLC., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: For patients with stage IV non-small-cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions and exon 21 L858R mutations, osimertinib is the standard of care. Investigating the activity and safety of osimertinib in patients with EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations is of clinical interest., Patients and Methods: Patients with stage IV non-small-cell lung cancer with confirmed EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations were eligible. Patients were required to have measurable disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were required to be EGFR tyrosine kinase inhibitor-naive. The primary objective was objective response rate, and secondary objectives were progression-free survival, safety, and overall survival. The study used a two-stage design with a plan to enroll 17 patients in the first stage, and the study was terminated after the first stage due to slow accrual., Results: Between May 2018 and March 2020, 17 patients were enrolled and received study therapy. The median age of patients was 70 years (interquartile range 62-76), the majority were female (n = 11), had a performance status of 1 (n = 10), and five patients had brain metastases at baseline. The objective response rate was 47% [95% confidence interval (CI) 23% to 72%], and the radiographic responses observed were partial response (n = 8), stable disease (n = 8), and progressive disease (n = 1). The median progression-free survival was 10.5 months (95% CI 5.0-15.2 months), and the median OS was 13.8 months (95% CI 7.3-29.2 months). The median duration on treatment was 6.1 months (range 3.6-11.9 months), and the most common adverse events (regardless of attribution) were diarrhea, fatigue, anorexia, weight loss, and dyspnea., Conclusions: This trial suggests osimertinib has activity in patients with these uncommon EGFR mutations., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Major advances in the diagnosis and treatment of non-small cell lung cancer (NSCLC) have resulted in a sharp decline in associated mortality rates, thereby propelling NSCLC to the forefront of precision medicine. Current guidelines recommend upfront comprehensive molecular testing for all known and actionable driver alterations/biomarkers ( EGFR , ALK , ROS1 , BRAF , KRAS , NTRK , MET , RET , HER2 [ ERBB2 ], and PD-L1), especially in advanced disease stages, as they significantly influence response to therapy. In particular, hybrid capture-based next-generation sequencing (HC-NGS) with an RNA fusion panel to detect gene fusions is a veritable requirement at both diagnosis and progression (resistance) of any-stage non-squamous adenocarcinoma NSCLCs. This testing modality ensures selection of the most timely, appropriate, and personalized treatment, maximization of therapeutic efficacy, and prevention of use of suboptimal/contraindicated therapy. As a complement to clinical testing and treatment, patient, family, and caregiver education is also key to early screening and diagnosis, access to care, coping strategies, positive outcomes, and survival. The advent of social media and increased internet access has amplified the volume of educational and support resources, consequently changing the dynamics of patient care. This review provides guidance on integration of comprehensive genomic testing with an RNA fusion panel as a global diagnostic standard for all adenocarcinoma NSCLC disease stages and provides key information on patient and caregiver education and resources., Competing Interests: LV has received grants or contracts from Takeda, Janssen, Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, InterVenn Biosciences, and Sanofi. MS has received grants or contracts from Genentech, Spectrum, Novartis, AstraZeneca, Daiichi Sankyo, and Cullinan; consulting fees from Lilly, Spectrum, Zeno, and Coherus; payment or honoraria from Genentech, Lilly, AstraZeneca, Blueprint, Janssen, Jazz, GSK, Regeneron, G1Therapeutics, and Guardant; and has a leadership or fiduciary role as the Lung Committee Co-Chair for Elsevier ClinPath. JW has stock or ownership interests in Achilles Therapeutics immediate family member, Nektar, Vesselon, Nuvalent, Lyell Immunopharma, En Fuego Therapeutics, and Vertex author; consulting or advisory role from AstraZeneca, EMD Serono, Genentech, G1 Therapeutics, Jounce Therapeutics, AbbVie, Nanobiotix, Azitra, Lilly, Blueprint Medicines, Pfizer, Saatchi Wellness, Jazz Pharmaceuticals, Boehringer Ingelheim, Regeneron, Genmab, SDP Oncology, BeiGene, and Merck author; research funding from Merck, AstraZeneca/Medimmune, G1 Therapeutics, Immunicum, Loxo/Lilly, Mirati Therapeutics, Sumitomo Dainippon Pharma Oncology, Boehringer Ingelheim, PDS Biotechnology institution; and travel, accommodations, expenses from Mirati Therapeutics author., (Copyright © 2023 Villaruz, Socinski and Weiss.)

Purpose: Resistance to immune checkpoint inhibition (ICI) in advanced non-small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types., Methods: In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity., Results: Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC., Conclusion: This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.

More than 50 years after the discovery of RAS family proteins, which harbor the most common activating mutations in cancer, the U.S. Food and Drug Administration approved the first direct allele-specific inhibitor of mutant KRAS in lung cancer. We highlight the history of discovering RAS and decades of studies targeting KRAS -driven lung cancer. A landmark article by Shokat and colleagues in 2013 elucidated allosteric inhibition of this undruggable target and paved the way for the first-in-class direct KRAS G12C inhibitor. Although these drugs have impressive 36%-45% objective response rates with a median duration of response of 10 months, many tumors do not respond, and diverse mechanisms of resistance have already been observed; this includes new KRAS alterations, activation of alternate RTK pathway proteins, bypass pathways, and transcriptional remodeling. These resistance mechanisms can be profiled using tissue-based and plasma-based testing and help to inform clinical trial options for patients. We conclude with a discussion of research informing ongoing clinical trials to rationally test promising treatments to thwart or overcome resistance to KRAS G12C inhibitors and target other KRAS -altered lung cancers.

Background: Brigatinib, a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is central nervous system (CNS) penetrant and active against anaplastic lymphoma kinase (ALK) resistance mutations. We prospectively studied the activity of brigatinib in patients with disease progression after second generation ALK TKIs., Methods: Patients with stage IIIB/IV ALK + non-small cell lung cancer (NSCLC), and progressive disease after second ALK TKIs were eligible. Cohort A enrolled patients with disease progression on any second ALK TKI, cohort B enrolled patients with disease progression after first-line therapy with alectinib, and cohort C enrolled patients who experienced disease progression on standard dose brigatinib. Brigatinib treatment was 90 mg daily for seven days and then escalated to 180 mg daily in cohorts A and B, and 240 mg daily in cohort C. The primary endpoint was objective response rate (ORR), and a 2-stage design was used. The intended enrollment was 20 patients in stage 1, and 20 patients in stage 2., Results: The study was closed due to slow accrual. Between March 2017 and June 2020, 32 patients received study therapy; three patients in cohort A moved to cohort C after initial progression for a total of 35 study subjects. Of the 32 patients, 16 (50%) were male, the median age was 55 years (range 32-76), and patients received a median number of 2 prior ALK TKI's (range 1-3). Cohort A enrolled 27 patients, cohort B enrolled four patients, and cohort C enrolled four patients. The ORR in cohorts A, B, and C was 33% (95% confidence interval (CI: 16% to 54%), 25% (95% CI: 0.63% to 81%), and 0%, respectively., Conclusion: Brigatinib has activity in ALK positive NSCLC patients with disease progression after second generation ALK TKIs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Final overall survival (OS) analyses are presented for EGFR mutations and liver or brain metastases subgroups in the phase 3 IMpower150 study (NCT02366143) evaluating atezolizumab plus bevacizumab plus carboplatin and paclitaxel (ABCP) or atezolizumab plus carboplatin and paclitaxel (ACP) versus bevacizumab plus carboplatin and paclitaxel (BCP)., Methods: Overall, 1202 patients (intention-to-treat population) with chemotherapy-naive, metastatic, nonsquamous NSCLC were randomized to ABCP, ACP, or BCP. Patients with treated, stable brain metastases were permitted. OS was evaluated in EGFR mutations and baseline liver metastases subgroups; rate and time to development of new brain metastases were evaluated in the intention-to-treat patients., Results: At data cutoff (September 13, 2019; median follow-up, 39.3 mo), OS improvements were sustained with ABCP versus BCP in sensitizing EGFR mutations (all: hazard ratio [HR] = 0.60; 95% confidence interval [CI]: 0.31-1.14; previous tyrosine kinase inhibitor [TKI]: HR = 0.74; 95% CI: 0.38-1.46) and baseline liver metastases (HR = 0.68; 95% CI: 0.45-1.02) subgroups. ACP did not have survival benefit versus BCP in sensitizing EGFR mutations (all: HR = 1.0; 95% CI: 0.57-1.74; previous TKI: HR = 1.22; 95% CI: 0.68-2.22) or liver metastases (HR = 1.01; 95% CI: 0.68-1.51) subgroups. Overall, 100 patients (8.3%) developed new brain metastases. Although not formally evaluated, an improvement toward delayed time to development was found with ABCP versus BCP (HR = 0.68; 95% CI: 0.39-1.19)., Conclusions: This final exploratory analysis revealed OS benefits for ABCP versus BCP in patients with sensitizing EGFR mutations, including those with previous TKI failures, and with liver metastases, although these results should be interpreted with caution. The impact of ABCP on delaying the development of new brain lesions requires further investigation., (Copyright © 2021 International Association for the Study of Lung Cancer. All rights reserved.)

Background: Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy., Methods: This open-label, multicentre, randomised, phase 2 trial was done by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a web-based system by the study statistician using a permuted block scheme (block sizes of three or six) without stratification to receive either durvalumab (1500 mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75 mg intravenously every 4 weeks for a maximum of four cycles) alone or with low-dose (0·5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered over three 8-Gy fractions during the first cycle only), 1 week after initial durvalumab-tremelimumab administration. Study treatment was continued until 1 year or until progression. The primary endpoint was overall response rate (best locally assessed confirmed response of a partial or complete response) and, along with safety, was analysed in patients who received at least one dose of study therapy. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete., Findings: Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled and randomly assigned, of whom 78 (26 per group) were treated. This trial was stopped due to futility assessed in an interim analysis. At a median follow-up of 12·4 months (IQR 7·8-15·1), there were no differences in overall response rates between the durvalumab-tremelimumab alone group (three [11·5%, 90% CI 1·2-21·8] of 26 patients) and the low-dose radiotherapy group (two [7·7%, 0·0-16·3] of 26 patients; p=0·64) or the hypofractionated radiotherapy group (three [11·5%, 1·2-21·8] of 26 patients; p=0·99). The most common grade 3-4 adverse events were dyspnoea (two [8%] in the durvalumab-tremelimumab alone group; three [12%] in the low-dose radiotherapy group; and three [12%] in the hypofractionated radiotherapy group) and hyponatraemia (one [4%] in the durvalumab-tremelimumab alone group vs two [8%] in the low-dose radiotherapy group vs three [12%] in the hypofractionated radiotherapy group). Treatment-related serious adverse events occurred in one (4%) patient in the durvalumab-tremelimumab alone group (maculopapular rash), five (19%) patients in the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea, hypokalemia, and respiratory failure), and four (15%) patients in the hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and hyponatremia). In the low-dose radiotherapy group, there was one death from respiratory failure potentially related to study therapy., Interpretation: Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting., Funding: The US National Institutes of Health and the Dana-Farber Cancer Institute., Competing Interests: Declaration of interests JDS declares research support paid to their institution from Merck, BMS, Regeneron, Debiopharm, and the NCI; consulting or participation on a scientific advisory board, and travel fees and payment for lectures from Genentech, Immunitas, Debiopharm, BMS, Nanobiotix, Tilos, AstraZeneca, LEK, Catenion, ACI Clinical, Astellas, Stimit, and Merck; expert witness fees from Pearson Doyle Mohre and Pastis, Kline and Specter, and Heidell, Pittoni, Murphy and Bach; stock options from Immunitas; and equity in Doximity. SMA declares research support paid to her institution from Merck, Exilixis, Abbvie, Kura Oncology, Amgen, and Nektar. RDG declares support for the present manuscript from a grant from the NCI of the National Institutes of Health (NIH); grants or contracts (to his institution) from Pfizer, Mirati, Daiichi Sankyo, Jounce Therapeutics, Helsinn, BMS, Merck, Janssen, and Takeda; honoraria from Rockpointe CME, Targeted Oncology, OncLive, and the Society for Immunotherapy of Cancer; reimbursement for travel for meetings from Pfizer and AstraZeneca; participation on advisory boards for Mirati, Daiichi Sankyo, AstraZeneca, Sanofi, Oncocyte, Jazz Pharmaceuticals, BluePrint Medicines, and Pfizer; and that he is co-chair of the Hoosier Cancer Research Network Thoracic Clinical Trial Working Group. CL declares honorarium for chairing the data and safety monitoring board for Delcath. JH declares participation on advisory boards for Bayer and Merck, and research funding from Merck, Boston Biomedical, Treos Bio, Senhwa Biosciences, Bayer, Incyte, TriOncology, Seattle Genetics, Hutchison MediPharma, Pionyr Immunotherapeutics, Trovogene, Taiho Pharmaceutical, Effector Therapeutics, and G1 Therapeutics. JLA declares research support from Pfizer; scientific advisory board membership for the Lustgarten Foundation, Stand Up to Cancer, Moleculin Biotech, Bessor Pharma, and Fujifilm; stock options from Bessor Pharma and Moleculin Biotech; and honoraria for data and safety monitoring board membership from Panbela Therapeutics and the Pancreatic Cancer Action Network. SKJ declares grant funding to her institution from the NCI and the Cancer Therapy Evaluation Program, and is a consultant and adjudication committee member for Merck, IMX Medical, and Syntactx. NVU has consulted for QED, Ipsen, Taiho, Incyte, AstraZeneca, and Astellas, and declares research funding from Taiho, Eli Lilly, Ipsen, and EMD Serono, and long position holdings in Natera and Exact Sciences. KLS is a member of the data and safety monitoring committee for the Case Comprehensive Cancer Center. JMJ declares consulting for Foundation Medicine. HP declares research grants or funding to their institution from Adlai Nortye USA, Alpine Immune Sciences, Ambrx, Amgen, Aprea Therapeutics, ArrayBioPharma, Bayer, BeiGene, BJ Bioscience, BMS, Daiichi Pharmaceutical, Eli Lilly, Elicio Therapeutics, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Hoffman-LaRoche, Hutchison MediPharma, ImmuneOncia Therapeutics, Incyte, Jounce Therapeutics, Mabspace Biosciences, MacroGenics, Medimmune, Medivation, Merck, Millennium, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, Pfizer, PsiOxus Therapeutics, Puma Biotechnology, Regeneron Pharmaceuticals, RePare Therapeutics, Seattle Genetics, Synermore Biologics, Taiho Pharmaceutical, TopAlliance Biosciences, TurningPoint Therapeutics, Vedanta Biosciences, and Xencor, and reimbursement for meetings or travel from Daiichi Sankyo and Vedanta. LCV declares consulting fees for Janssen, BMS, Takeda, Jazz, and Daiichi Sankyo. JLW declares research support from the NCI of the NIH. RHM declares research support from ViewRay and AstraZeneca; scientific advisory board participation for ViewRay and AstraZeneca; and expert witness fees from the US Attorney's Office Northern District of New York. MarMA has consulted for Genentech, BMS, Merck, AstraZeneca, Maverick, Blueprint Medicine, Syndax, Ariad/Takeda, Nektar, Gritstone, ArcherDX, Mirati, NextCure, Novartis, EMD Serono, and Panvaxal/NovaRx; declares research funding (to their institute) from AstraZeneca, Lilly, Genentech, BMS, and Merck; and declares participation on a data safety monitoring board and advisory board for BMS and Apollomics. SJR declares research support from BMS, Merck, Affimed, and KITE/Gilead, is on the Scientific Advisory Board of Immunitas Therapeutics, and has equity in Immunitas Therapeutics. AMM declares research support from Merck, BMS, Transgene, Incyte, Trisalus, Genentech, and the NIH; consulting fees from Zosano; advisory board participation for BMS, AstraZeneca, Incyte, and Dynavax; and stock options in MultiplexThera. CJW declares equity in BioNTech, U24 research support from the NCI of the NIH, and research funding from Pharmacyclics. FSH declares research support from the NCI of the NIH, BMS, Novartis, and Genentech; royalties or licenses from BMS and Novartis; consulting fees from BMS, EMD Serono, Surface, Sanofi, Genentech, Gossamer, Trillium, Immunocore, Merck, Novartis, Compass Therapeutics, Pieris, Bioentre, Iovance, Catalym, and Amgen; patents for the methods for treating MHC class I polypeptide-related sequence A disorders (number 20100111973; with royalties paid), tumour antigens and uses thereof (number 7250291; issued), angiopoiten-2 biomarkers predictive of anti-immune checkpoint response (number 20170248603; pending), compositions and methods for the identification, assessment, prevention, and treatment of melanoma using PD-L1 isoforms (number 20160340407; pending), therapeutic peptides (number 20160046716; pending), therapeutic peptides (number 20140004112; pending), therapeutic peptides (number 20170022275; pending), therapeutic peptides (number 20170008962; pending), therapeutic peptides (number 9402905; issued), methods of using pembrolizumab and trebananib (pending), vaccine compositions and methods for restoring NKG2D pathway function against cancers (number 10279021; issued), antibodies that bind to MHC class I polypeptide-related sequence A (number 10106611; issued), and anti-galectin antibody biomarkers predictive of anti-immune checkpoint and anti-angiogenesis responses (number 20170343552; pending); data safety monitoring board and advisory board participation for Aduro and Checkpoint Therapeutics; scientific advisory board leadership for Bicara and Apricity; and stock options in Checkpoint Therapeutics, Pionyr, Apricity, and Bicara. AL is currently an employee of Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data., Methods: Pretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety., Results: At data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5-78.5) and 16.3 (range: 0.4-80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8-80.1) and 63.9% (46.2-79.2), median progression-free survival (95% CI) was 10.2 (6.9-16.7) and 10.8 (7.0-14.5) months, and median overall survival (95% CI) was 18.2 (14.3-28.6) and 17.3 (12.3-40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation., Conclusions: Dabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the relationship between macrovasculature features and the standardized uptake value (SUV) of positron emission tomography (PET), which is a surrogate for the metabolic activity of a lung tumor., Methods: We retrospectively analyzed a cohort of 90 lung cancer patients who had both chest CT and PET-CT examinations before receiving cancer treatment. The SUVs in the medical reports were used. We quantified three macrovasculature features depicted on CT images (i.e., vessel number, vessel volume, and vessel tortuosity) and several tumor features (i.e., volume, maximum diameter, mean diameter, surface area, and density). Tumor size (e.g., volume) was used as a covariate to adjust for possible confounding factors. Backward stepwise multiple regression analysis was performed to develop a model for predicting PET SUV from the relevant image features. The Bonferroni correction was used for multiple comparisons., Results: PET SUV was positively correlated with vessel volume (R = 0.44, p < 0.001) and vessel number (R = 0.44, p < 0.001) but not with vessel tortuosity (R = 0.124, p > 0.05). After adjusting for tumor size, PET SUV was significantly correlated with vessel tortuosity (R = 0.299, p = 0.004) and vessel number (R = 0.224, p = 0.035), but only marginally correlated with vessel volume (R = 0.187, p = 0.079). The multiple regression model showed a performance with an R-Squared of 0.391 and an adjusted R-Squared of 0.355 (p < 0.001)., Conclusions: Our investigations demonstrate the potential relationship between macrovasculature and PET SUV and suggest the possibility of inferring the metabolic activity of a lung tumor from chest CT images., (© 2021 American Association of Physicists in Medicine.)

Introduction: MET amplification is a rare, potentially actionable, primary oncogenic driver in patients with NSCLC., Methods: The influence of MET amplification on the clinical activity of the ALK, ROS1, and MET inhibitor, crizotinib (250 mg twice daily), was examined in patients with NSCLC (NCT00585195) who were enrolled into high (≥4 MET-to-CEP7 ratio), medium (>2.2 to <4 MET-to-CEP7 ratio), or low (≥1.8 to ≤2.2 MET-to-CEP7 ratio) amplification categories. Retrospective next-generation sequencing profiling was performed on archival tumor tissue. End points included objective response rate (ORR), duration of response, and progression-free survival., Results: A total of 38 patients with a MET-to-CEP7 ratio greater than or equal to 1.8 by local fluorescence in situ hybridization testing received crizotinib. All patients were response-assessable, among whom 21, 14, and 3 had high, medium, and low MET amplification, respectively. ORRs of 8 of 21 (38.1%), 2 of 14 (14.3%), and 1 of 3 (33.3%), median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival values of 6.7, 1.9, and 1.8 months were observed for those with high, medium, and low MET amplification, respectively. MET amplification gene copy number greater than or equal to 6 was detected by next-generation sequencing in 15 of 19 (78.9%) analyzable patients. Of these 15 patients, objective responses were observed in six (40%), two of whom had concurrent MET exon 14 alterations. No responses were observed among five patients with concurrent KRAS, BRAF, or EGFR mutations., Conclusions: Patients with high-level, MET-amplified NSCLC responded to crizotinib with the highest ORR. Use of combined diagnostics for MET and other oncogenes may potentially identify patients most likely to respond to crizotinib., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Osimertinib is an effective therapy in EGFR -mutant non-small cell lung cancer (NSCLC), but resistance invariably develops. Navitoclax is an oral inhibitor of BCL-2/BCL-xL that has exhibited synergy with osimertinib in preclinical models of EGFR -mutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance., Patients and Methods: This single-arm phase Ib study evaluated safety, tolerability, and feasibility of osimertinib and navitoclax, including dose expansion in T790M-positive patients at the recommended phase II dose (RP2D). Eligible patients had advanced EGFR -mutant NSCLC with prior tyrosine kinase inhibitor exposure. Five dose levels were planned with osimertinib from 40 to 80 mg orally daily and navitoclax from 150 to 325 mg orally daily., Results: A total of 27 patients were enrolled (18 in the dose-escalation cohort and nine in the dose-expansion cohort): median age 65, 67% female, 48% exon 19 del, and 37% L858R, median one prior line of therapy. The most common adverse events were lymphopenia (37%), fatigue (22%), nausea (22%), and thrombocytopenia (37%). No dose-limiting toxicities were seen in dose-escalation cohort; osimertinib 80 mg, navitoclax 150 mg was chosen as the RP2D. Most patients (78%) received >95% of planned doses through three cycles. In expansion cohort, objective response rate was 100% and median progression-free survival was 16.8 months. A proapoptotic effect from navitoclax was demonstrated by early-onset thrombocytopenia., Conclusions: Oral combination therapy with navitoclax and osimertinib was safe and feasible at RP2D with clinical efficacy. Early thrombocytopenia was common, supporting an target engagement by navitoclax. Further study of BCL-2/BCL-xL inhibition to enhance osimertinib activity is warranted., (©2020 American Association for Cancer Research.)

Patients with oncogene-driven lung cancer have limited therapeutic options after progressing on their targeted tyrosine kinase inhibitor (TKI) therapy. Given the growing role of immune checkpoint inhibitor (ICI) therapy in the treatment of lung cancer, oncogene-driven cancer has warranted further evaluation regarding ICI therapy. However, initial ICI studies have suggested that ICI monotherapy is not only lacking in efficacy, but that it may be less tolerable in oncogene-driven non-small-cell lung cancer (NSCLC). We performed a detailed review of the literature using Pubmed, and present the current and impactful findings here. Studies evaluating the use of concurrent ICI therapy and TKI therapy have also suggested increased toxicity and lack of increased activity in these patients. Larger studies have suggested that the sequence of ICI therapy and TKI, such as utilizing ICI therapy after TKI as opposed to before TKI, may play a role in reducing toxicity (hepatotoxicity, pneumonitis); however, these studies are limited in number. Novel methods of patient selection, including low tumor mutational burden, inflamed phenotyping, and  high CD8 + tumor infiltrating lymphocytes, may aid in determining ideal patients to give ICI therapy. Novel therapeutic combinations including the addition of anti-VEGF (vascular endothelial growth factor) therapy or radiotherapy show promising findings for these patients. Given the growing unmet need for therapeutic options in patients with oncogene-driven NSCLC who have failed TKI therapy, further research is warranted.

Background: The selection of later-line treatment for older patients with AJCC (version 7) stage IV non-small cell lung cancer (NSCLC) remains controversial. Nanoparticle albumin-bound (nab)-paclitaxel is approved with carboplatin for the first-line treatment of patients with NSCLC and subgroup analysis of phase 3 data has suggested superior survival in older patients., Methods: The authors conducted a phase 2 study of nab-paclitaxel in 42 patients aged ≥70 years who had been treated previously with a platinum doublet regimen; patients also could have received a PD-1 inhibitor. The primary endpoint of the current study was grade 3 to 5 toxicity (according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). In addition to response rate, progression-free survival (PFS), and overall survival (OS), geriatric assessments also were performed before and during treatment, associations between baseline sarcopenia and outcomes were explored, and changes in T lymphocyte p16 before and during treatment were measured. The authors also performed a retrospective subgroup analysis of 19 older patients who were treated with nab-paclitaxel as part of a larger, randomized, phase 2 study; data were not combined., Results: The rate of grade 3 to 5 toxicities was 33.7%. The most common grade 3 to 5 toxicities were decreased white blood cell count (11.9%), neutropenia (9.5%), and fatigue (11.9%). The response rate was 34.2% (2.6% complete response rate and 31.6% partial response rate). The median PFS was 5.2 months and the median OS was 9.3 months. Adverse prognostic factors were common: 42% of patients were frail and 39% of patients were prefrail, whereas 21% had an Eastern Cooperative Oncology Group performance status of 2 and 27% were sarcopenic. Only frailty was found to be predictive of inferior survival. A subgroup analysis of 19 older patients treated with nab-paclitaxel alone in a prior trial demonstrated a response rate of 15.8%, a PFS of 4.2 months, and an OS of 13.6 months., Conclusions: Fit and prefrail older patients with stage IV NSCLC should be considered for treatment with nab-paclitaxel after disease progression with doublet chemotherapy., (© 2020 American Cancer Society.)

MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs) 1 . These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition 2 . Crizotinib is a multikinase inhibitor with potent activity against MET 3 . The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC.

Objectives: Necitumumab is a second-generation, recombinant, human IgG1-type monoclonal antibody directed against EGFR approved for adult patients with metastatic squamous non-small cell lung cancer (NSCLC) in combination with gemcitabine and cisplatin. This study assessed the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) and carboplatin in combination with necitumumab as first-line therapy in patients with stage IV squamous NSCLC., Materials and Methods: The treatment regimen comprised triplet induction with necitumumab (800 mg) with nab-paclitaxel (100 mg/m 2 ) and carboplatin (AUC 6 mg*min/mL) for 4 cycles, followed by doublet maintenance with necitumumab and nab-paclitaxel with a 3-weekly schedule until progressive disease or unacceptable toxicity. The primary endpoint of the study was objective response rate (ORR)., Results: Fifty-four patients were enrolled. Median age was 65 years (range, 47-80 years). The majority of the patients were male (n = 42 [77.8%]) with an ECOG PS of 1 (n = 42 [77.8%]). The ORR was 51% (n = 26/54), and the disease control rate was 78.4% (n = 40/54). Median overall survival (OS) was 15.5 months (95% confidence interval [CI]: 10.18-not calculable), and the OS rate at 12 months was 50.4% (95% CI: 29.0-68.4). Median progression-free survival was 5.6 months (95% CI: 4.24-7.69)]. The most frequently reported treatment-emergent adverse events were anemia (57.4%), fatigue (55.6%), neutrophil count decreased (55.6%), hypomagnesemia (44.4%), and rash (38.9%)., Conclusion: Necitumumab/nab-paclitaxel/carboplatin first-line therapy produced favorable efficacy outcomes with manageable toxicity in patients with stage IV squamous NSCLC. The safety profile was fairly comparable with previous necitumumab combination studies in lung cancer., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Combination immunotherapy may result in improved antitumor activity compared with single-agent treatment. We report results from dose-finding and dose-expansion cohorts of the phase 1/2 KEYNOTE-021 study that evaluated combination therapy with anti‒programmed death 1 (PD-1) antibody pembrolizumab plus anti‒cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in patients with previously treated advanced non-small-cell lung cancer (NSCLC)., Materials and Methods: Eligibility criteria stipulated histologically/cytologically confirmed advanced NSCLC and treatment failure on ≥1 prior systemic therapy (platinum-based chemotherapy or targeted therapy for patients with EGFR/ALK aberrations). In the dose-finding cohort, patients initially received pembrolizumab 10 mg/kg plus ipilimumab 1 or 3 mg/kg once every 3 weeks for 4 cycles followed by pembrolizumab 10 mg/kg monotherapy for up to 2 years. Based on emerging published data, subsequent patients received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg. Objective response rate (ORR; primary efficacy endpoint) was assessed per RECIST version 1.1 by blinded, independent central review. Phase 2 hypothesis that ORR would be greater than the 20% rate for historical controls was evaluated using the exact binomial test., Results: Fifty-one patients were enrolled; 71% received ≥2 prior lines of therapy. No dose-limiting toxicities occurred at any dose level. Among patients who received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg (n = 44), ORR was 30% (95% CI, 17%-45%), but not statistically significantly >20% (P = 0.0858). Median progression-free survival in this group was 4.1 (95% CI, 1.4-5.8) months; median overall survival was 10.9 (95% CI, 6.1-23.7) months. With pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg, incidences of treatment-related adverse events, grade 3-5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions were 64%, 29%, and 42%, respectively., Conclusions: In patients with heavily pretreated advanced NSCLC, pembrolizumab plus ipilimumab showed evidence of antitumor activity, but was associated with meaningful toxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Several studies have demonstrated analytical comparability between different PD-L1 assays, but their clinical validity in non-small-cell lung cancer in terms of response to treatment outside clinical trials has not been established. The aim of our study is to assess the analytical performance of laboratory-developed tests for Ventana SP263 and Agilent/Dako 22C3, and to investigate the association between PD-L1 assays and response to PD-1/L1 inhibitors., Methods and Results: PD-L1 SP263 and 22C3 assays were performed on 302 consecutive non-small-cell lung carcinoma samples Both assays were optimised for use on the automated Ventana BenchMark Ultra platform. Scoring algorithms for staining of the tumour cells using the established cut-offs were applied to all samples. Best overall response (BOR) for 44 patients treated with either nivolumab, pembrolizumab or atezolizumab were assessed using recist version 1.1 and correlated with PD-L1 assay results. Assays showed good agreement, with a concordance correlation coefficient of 0.86 [95% confidence interval (CI) = 0.82-0.90)]. Comparing the assays using cut-offs of 1%, 5%, 10%, 1-49% and ≥50% showed an association between the two assays (P < 0.0001). The SP263 10% cut-off (P = 0.032) was associated with BOR, whereas the 1% (P = 0.087) and 5% (P = 0.051) cut-offs were not. In contrast 22C3, cut-offs of 1% (P = 0.019), 5% (P = 0.025) and 10% (P = 0.014) were all associated with BOR., Conclusions: The SP263 and 22C3 LDTs demonstrated good analytical concordance, and correlation with response to PD-1/L1 inhibitors., (© 2018 John Wiley & Sons Ltd.)

Objectives: Platinum-based chemotherapy for advanced non-small-cell lung cancer (NSCLC) has modest benefit overall, but has the potential to amplify immune responses. In cohorts A-C of the multicohort phase 1/2 study KEYNOTE-021 (Clinicaltrials.gov, NCT02039674), we evaluated combinations of platinum-doublet chemotherapy with the anti-programmed death 1 monocloncal antibody pembrolizumab., Materials and Methods: Patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations were randomized to pembrolizumab 2 or 10 mg/kg Q3W plus carboplatin area under the serum concentration-time curve (AUC) 6 mg/mL/min plus paclitaxel 200 mg/m 2 (cohort A, any histology), carboplatin AUC 6 mg/mL/min plus paclitaxel 200 mg/m 2 plus bevacizumab 15 mg/kg (cohort B, non-squamous), or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m 2 (cohort C, non-squamous) for 4 cycles followed by maintenance pembrolizumab (cohort A), pembrolizumab plus bevacizumab (cohort B), or pembrolizumab plus pemetrexed (cohort C). Response was assessed by blinded independent central review., Results: Overall, 74 patients were randomized; median follow-up was 21.4, 16.4, and 17.4 months in cohorts A, B, and C, respectively. No dose-limiting toxicities occurred in any cohort at either pembrolizumab dose. Most frequent treatment-related adverse events (AEs) were alopecia, fatigue, and nausea. Treatment-related grade 3/4 AEs occurred in 40%, 42%, and 46% of patients in cohorts A, B, and C, respectively; AEs with possible immune etiology occurred in 24%, 50%, and 38% of patients, respectively. Objective response rates were 48%, 56%, and 75% in cohorts A, B, and C, respectively., Conclusion: Pembrolizumab in combination with carboplatin-paclitaxel and with pemetrexed-carboplatin yielded encouraging antitumor activity and toxicity consistent with known toxicities of platinum-based chemotherapy or pembrolizumab monotherapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: The phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified nab -paclitaxel/carboplatin regimen for patients with advanced non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2., Methods: Chemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of nab -paclitaxel 100 mg/m 2 days 1 and 8 plus carboplatin area under the curve 5 day 1 q3w (induction). Patients without progression received nab -paclitaxel monotherapy (100 mg/m 2 days 1 and 8 q3w) until progression/unacceptable toxicity. Primary endpoint: percentage of patients discontinuing induction due to treatment-emergent adverse events (TEAEs)., Results: 11/40 treated patients (27.5%; 95% CI, 14.60-43.89) discontinued chemotherapy induction due to TEAEs; 16/40 (40.0%) continued nab -paclitaxel monotherapy. Median progression-free and overall survival were 4.4 (95% CI, 2.99-7.00) and 7.7 (95% CI, 4.93-13.17) months. Grade 3/4 TEAEs during induction included neutropenia (22.5%), anemia (17.5%), thrombocytopenia (5.0%), and peripheral neuropathy (2.5%)., Conclusion: This nab -paclitaxel-based regimen was tolerable in patients with advanced NSCLC and ECOG PS 2, with efficacy comparable to historical chemotherapy data.

Introduction: Bavituximab is an immunomodulatory chimeric monoclonal antibody that inhibits phosphatidylserine signaling, which promotes innate and adaptive immune responses. In this phase Ib trial we evaluated the safety, tolerability, and preliminary antitumor activity of pemetrexed, carboplatin, bavituximab in advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with advanced nonsquamous NSCLC and performance status 0 or 1 were treated with pemetrexed 500 mg/m 2 and carboplatin area under the curve 6 once every 3 weeks for up to 6 cycles, with concurrent bavituximab (0.3, 1, or 3 mg/kg) intravenously weekly, using a standard 3+3 design. At the maximum identified dose, additional patients were enrolled to further characterize the safety profile. The primary objective was to characterize the safety, determine the dose-limiting toxicities (DLTs), and establish the recommended phase II dose of bavituximab in combination with pemetrexed and carboplatin in incurable stage IV nonsquamous NSCLC., Results: Between March 29, 2011 and December 30, 2013, 26 patients were enrolled. Three patients each were enrolled into dose escalation cohorts of bavituximab (0.3, 1, and 3 mg/kg). Therapy was well tolerated with no DLTs, and toxicities were consistent with those expected from pemetrexed/carboplatin. Overall response was 28%, with a median progression-free and overall survival of 4.8 months and 12.2 months, respectively., Conclusion: The combination of pemetrexed, carboplatin, bavituximab is well tolerated. However, with toxicities and preliminary efficacy signal similar to pemetrexed/carboplatin alone, further studies of bavituximab should focus on ways to enhance its immunomodulatory role., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas. Experimental Design: Sixteen U.S. institutions enrolled 1,367 patients with lung cancer in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and IHC. Results: The use of targeted therapies in patients with EGFR, ERBB2, or BRAF p.V600E mutations, ALK, ROS1 , or RET rearrangements, or MET amplification was associated with a survival increment of 1.5 years compared with those with such mutations not receiving targeted therapy, and 1.0 year compared with those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in EGFR / ALK / ROS1 , when compared with 75 never smokers with the same alterations. In addition, coexisting TP53 mutations were associated with shorter survival among patients with EGFR, ALK , or ROS1 alterations. Conclusion: Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment. Clin Cancer Res; 24(5); 1038-47. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Immunotherapy with programmed death 1 (PD-1)- and programmed death-ligand 1 (PD-L1)-targeted monoclonal antibodies has dramatically changed the therapeutic and prognostic landscape for several types of malignancy. PD-1 and PD-L1 are immune checkpoint proteins whose binding ultimately result in T cell exhaustion and self-tolerance. Blocking this pathway 'releases the brakes' on the immune system and allows for attack of tumor cells that express PD-L1. The clinical trials that led to the US Food and Drug Administration (FDA) approval of these agents used different immunohistochemical (IHC) platforms with various PD-L1 antibodies to assess for PD-L1 expression on either tumor cells or tumor-infiltrating immune cells. There are four PD-L1 IHC assays registered with the FDA, using four different PD-L1 antibodies (22C3, 28-8, SP263, SP142), on two different IHC platforms (Dako and Ventana), each with their own scoring systems. Attempts at harmonization of PD-L1 IHC antibodies and staining platforms are underway. While PD-L1 IHC can be used to predict the likelihood of response to anti-PD-1 or anti-PD-L1 therapy, a proportion of patients that are negative can have a response and identification of alternative biomarkers is critical to further refine selection of patients most likely to respond to these therapies.

Background: Activation of the mesenchymal-epidermal transition factor (MET) tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was evaluated in patients with metastatic, previously treated non-small cell lung cancer., Methods: In phase 1, a dose de-escalation design was adopted with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg daily. In phase 2, the disease control rate (DCR) (according to Response Evaluation Criteria in Solid Tumors) of the combination was evaluated using a Simon 2-stage design. The biomarkers examined included 10 plasma-circulating molecules associated with the EGFR and MET pathways., Results: Without indications for de-escalation, the recommended phase 2 dose was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid progression (hazard ratio, 2.14; 95% CI, 1.48-3.08)., Conclusions: Combined rilotumumab and erlotinib had an acceptable safety profile, and the DCR met the prespecified criteria for success. In the EGFR WT group, the DCR exceeded published reports for erlotinib alone. High circulating levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 2017;123:2936-44. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC., Methods: We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more., Results: Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy., Conclusions: Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).

Molecular profiling and the discovery of drugs that target specific activating mutations have allowed the personalization of treatment for non-small cell lung cancer (NSCLC). The epithelial growth factor receptor (EGFR) is frequently over-expressed and/or aberrantly activated in different cancers, including NSCLC. The most common activating mutations of EGFR in NSCLC fall within the tyrosine kinase-binding domain. Three oral EGFR tyrosine kinase inhibitors (TKIs) have been approved by the U.S. Food and Drug Administration (FDA) for first-line use in patients with EGFR mutation-positive NSCLC (exon 19 deletions or exon 21 [L858R] substitution mutations), as detected by an FDA-approved test. However, disease progression is common and is often the result of secondary mutations, of which the EGFR T790M mutation is the most prevalent. Few options were available upon progression until the introduction of osimertinib, a kinase inhibitor that targets the T790M mutation, which was recently approved for use in patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who progressed on or after EGFR TKI therapy. With the introduction of osimertinib, outcomes can now be improved in select patients. Therefore, performing a biopsy at progression to determine the underlying molecular cause of the acquired resistance is important for the enabling of individualized options that may provide the greatest opportunity for improved outcomes. This review discusses the latest updates in molecular testing at progression and outlines treatment options for this difficult-to-treat population., The Oncologist: 2017;22:3-11 IMPLICATIONS FOR PRACTICE: Although the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)-gefitinib, erlotinib, and afatinib-have changed the treatment paradigm for non-small cell lung cancer among those with EGFR mutation positive disease, most patients experience progression after approximately 12 months of treatment. Until recently, options were limited for patients who progressed, but improvements in molecular profiling and the approval of osimertinib, which targets the resistance mutation T790M, afford the opportunity for improved outcomes in many patients with this mutation. This article explains the options available after progression on initial EGFR TKI therapy and the importance of molecular testing at progression in making treatment decisions., (© AlphaMed Press 2016.)

Break-apart ALK FISH probe is the FDA approved approach for detection of ALK rearrangements in lung carcinoma patients who may benefit from ALK kinase inhibitors. The FISH assay can be technically challenging and difficult to interpret. ALK immunohistochemistry and next generation sequencing have been proposed as alternative approaches. In this study, we compared various ALK -FISH patterns to next -generation sequencing (NGS) for gene fusion detection, ALK immunohistochemistry (IHC) and tumor responses to crizotinib. 72 (4%) of 2116 lung adenocarcinoma were positive by ALK- FISH. Of 28 ALK-FISH positive cases selected for the study, FISH patterns included 15 (54%) cases with split signal, 10 (36%) with single orange signal and 3 (10%) with "mixed pattern". 12 (80%) cases with split signal and 4 (40%) cases with single orange signal were positive by NGS and IHC, while mixed cases were all negative. Mutation analysis of discordant cases revealed multiple mutations including oncogenic mutations in EGFR, KRAS, BRAF and ATM genes. All discordant cases in groups with split and mixed signal showed a lower number of cells with rearrangement (mean 28.5%; range 20.5-36.9%). No statistically significant association between response to crizotinib and FISH patterns was observed (p=0.73). In contrast, NGS fusion positive cases were associated with more responses to crizotinib than NGS negative cases (p= 0.016). Our study suggests that ALK FISH alone may not be the most reliable assay for detection of ALK gene rearrangements, and probably should be used in parallel with ALK IHC and NGS for detection of gene fusions and mutations.

Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000's of patients with ATM-deficient lung adenocarcinoma every year., Competing Interests: None. Helen Jones, Neil Smith, Mark O'Connor and Andrew Pierce are employees of AstraZeneca as clearly stated in author affiliations.

Immunotherapy has revolutionized the therapeutic landscape of advanced lung cancer. The adaptive immune system has developed a sophisticated method of tumor growth control, but T-cell activation is regulated by various checkpoints. Blockade of the immune checkpoints with therapies targeting the PD-1 pathway, such as nivolumab and pembrolizumab, has been validated as a therapeutic approach in non-small cell lung cancer. Newer therapies and novel combinations are also being evaluated, and the use of biomarkers in conjunction with these drugs is an area of active investigation. This review summarizes the current evidence for the efficacy and safety of the above approaches in the treatment of lung cancer.

Nab-paclitaxel is a novel therapeutic agent, which was approved in combination with carboplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC) regardless of histologic subtype in the United States of America by the Food and Drug Administration in 2012 and by the European Commission in 2015. This approval was based on the results of a phase III clinical trial showing superior response rates compared with solvent-based paclitaxel in combination with carboplatin. This review will focus on the early development and clinical data to date supporting the use of nab-paclitaxel in advanced NSCLC. The clinical question central to this review is whether nab-paclitaxel has a place in the current therapeutic landscape of advanced NSCLC., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Bevacizumab- and pemetrexed-based therapies have demonstrated activity in patients with non-small-cell lung cancer (NSCLC) and nonsquamous histologic features. Patients with history of never or light smoking might derive greater benefit from these therapies., Patients and Methods: The included patients had stage IIIB (malignant pleural effusion) or IV NSCLC with nonsquamous histologic features, adequate organ function, no contraindications to bevacizumab, and no previous cytotoxic therapy. The patients had also never smoked or had smoked ≤ 10 pack years and had quit ≥ 1 year before enrollment. The patients had received 4 cycles of carboplatin (area under the curve, 6), pemetrexed 500 mg/m(2), and bevacizumab 15 mg/kg. Patients without disease progression initiated maintenance therapy with pemetrexed and bevacizumab. A single-arm phase II trial with the primary endpoint of progression-free survival (PFS) was performed. The secondary endpoints were the objective response rate (ORR), overall survival (OS), and toxicity., Results: From March 2010 to November 2013, 38 eligible patients were enrolled and treated in the trial. The most common histologic type was adenocarcinoma (97%). Most of the patients were women (66%) and never smokers (63%). The median PFS was 12.6 months (95% confidence interval [CI], 8.0-23.9 months). The ORR and OS were 47% (95% CI, 31%-64%) and 20.3 months (95% CI, 15.8-30.5 months). The grade 3 or 4 toxicities occurring at rate of ≥ 10% were neutropenia (18%), anemia (16%), fatigue (16%), hypertension (16%), and thrombocytopenia (11%)., Conclusion: The combination of the carboplatin, pemetrexed, and bevacizumab demonstrated activity with acceptable toxicity in patients with a clinical history of never or light smoking., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Carboplatin/paclitaxel (CP), with or without sorafenib, result in objective response rates of 18-20 % in unselected chemotherapy-naïve patients. Molecular predictors of survival and response to CP-based chemotherapy in metastatic melanoma (MM) are critical to improving the therapeutic index. Intergroup trial E2603 randomized MM patients to CP with or without sorafenib. Expression data were collected from pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor tissues from 115 of 823 patients enrolled on E2603. The selected patients were balanced across treatment arms, BRAF status, and clinical outcome. We generated data using Nanostring array (microRNA (miRNA) expression) and DNA-mediated annealing, selection, extension and ligation (DASL)/Illumina microarrays (HT12 v4) (mRNA expression) with protocols optimized for FFPE samples. Integrative computational analysis was performed using a novel Tree-guided Recursive Cluster Selection (T-ReCS) [1] algorithm to select the most informative features/genes, followed by TargetScan miRNA target prediction (Human v6.2) and mirConnX [2] for network inference., Results: T-ReCS identified PLXNB1 as negatively associated with progression-free survival (PFS) and miR-659-3p as the primary miRNA associated positively with PFS. miR-659-3p was differentially expressed based on PFS but not based on treatment arm, BRAF or NRAS status. Dichotomized by median PFS (less vs greater than 4 months), miR-659-3p expression was significantly different. High miR-659-3p expression distinguished patients with responsive disease (complete or partial response) from patients with stable disease. miR-659-3p predicted gene targets include NFIX, which is a transcription factor known to interact with c-Jun and AP-1 in the context of developmental processes and disease., Conclusions: This novel integrative analysis implicates miR-659-3p as a candidate predictive biomarker for MM patients treated with platinum-based chemotherapy and may serve to improve patient selection.

Recognition of the vascular endothelial growth factor (VEGF) pathway as a key mediator of angiogenesis has led to the clinical study of several VEGF and VEGF receptor (VEGFR) targeted therapies in non-small-cell lung cancer (NSCLC). These targeted therapies include neutralizing antibodies to VEGF (bevacizumab and aflibercept) and VEGFR-2 (ramucirumab) and tyrosine kinase inhibitors (TKIs) with selectivity for the VEGFRs. Bevacizumab and ramucirumab are associated with survival advantages in the treatment of advanced NSCLC: bevacizumab in the first-line setting in combination with carboplatin/paclitaxel and ramucirumab in combination with docetaxel in the second-line setting. The VEGFR-2 TKIs have been associated with responses and improved progression-free survival in selected NSCLC settings; however, this level of activity has thus far been insufficient to confer significant survival advantages. This review will focus on the current state of VEGF targeted therapies in NSCLC.

Background: The advent of effective targeted therapy for BRAF(V600E) -mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced-stage BRAF-mutant lung adenocarcinomas., Methods: Data were reviewed for patients with advanced lung adenocarcinomas enrolled in the Lung Cancer Mutation Consortium whose tumors underwent testing for mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), human epidermal growth factor receptor 2 (HER2), AKT1, BRAF, dual-specificity mitogen-activated protein kinase kinase 1 (MEK1), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA); for anaplastic lymphoma kinase (ALK) translocations; and for MET amplification., Results: Twenty-one BRAF mutations were identified in 951 patients with adenocarcinomas (2.2%; 95% confidence interval [CI], 1.4%-3.4%): 17 (81%; 95% CI, 60%-92%) were BRAF(V600E) mutations, and 4 were non-BRAF(V600E) mutations. Among the 733 cases tested for all 10 genes, BRAF mutations were more likely to occur than most other genotypic abnormalities in current or former smokers (BRAF vs sensitizing EGFR, 82% vs 36%, mid-P < .001; BRAF vs ALK, 39%, mid-P = .003; BRAF vs other mutations, 49%, mid-P = .02; BRAF vs patients with more than 1 oncogenic driver [doubleton], 46%, mid-P = .04.) The double-mutation rate was 16% among patients with BRAF mutations but 5% among patients with other genomic abnormalities (mid-P = .045). Differences were not found in survival between patients with BRAF mutations and those with other genomic abnormalities (P > .20)., Conclusions: BRAF mutations occurred in 2.2% of advanced-stage lung adenocarcinomas, were most commonly V600E, and were associated with distinct clinicopathologic features in comparison with other genomic subtypes and with a high mutation rate in more than 1 gene. These findings underscore the importance of comprehensive genomic profiling in assessing patients with advanced lung adenocarcinomas., (© 2014 American Cancer Society.)

Objectives: Platinum-based chemotherapy with bevacizumab is a standard therapy for patients with stage IIIB/IV non-small cell lung cancer (NSCLC) with non-squamous (NS) histology. Mechanisms of resistance to bevacizumab include increased VEGF signaling or activation of VEGF receptors. Pazopanib is a multi-targeted VEGF receptor tyrosine kinase with single agent activity in NSCLC., Materials and Methods: Stage IIIB/IV patients with adequate organ function, who progressed on a bevacizumab containing therapy were eligible if it had been ≤8 weeks since the last bevacizumab treatment. The primary end-point was disease control rate (DCR), defined as partial or complete response, or stable disease for ≥12 weeks. Patients were assessed radiographically every 2 cycles (6 weeks). A Simon 2-stage design was used, and if in the first stage ≤4 of 17 patients experienced disease control the trial was to have been stopped for futility. An unplanned analysis was performed after 15 patients were evaluable secondary to slow accrual., Results: Between December 2010 and November 2013, 15 patients were treated on trial. The median age was 61 years (range 39-74), and all patients had stage IV disease. Of the 15 patients, 4 discontinued therapy prior to cycle 2 evaluation due to adverse events (n=3) and medical illness (n=1), 5 patients had progressive disease, 4 patients had stable disease for <12 weeks, and 2 patients had stable disease for ≥12 weeks. No responses were observed. The DCR observed was 13% (2/15), and the trial did not meet the criteria to proceed to the second stage. Episodes of grade 3 treatment related toxicities observed included: increased ALT (n=2), increased AST (n=1), anorexia (n=3), fatigue (n=3), hypertension (n=1), infection (n=1), mucositis (n=2), nausea (n=3), pericardial effusion (n=1), and vomiting (n=1)., Conclusion: Pazopanib has limited activity in NSCLC-NS in patients who have experienced disease progression on bevacizumab., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)