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Background: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC)., Methods: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR -mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review., Results: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR -related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib., Conclusions: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR -mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.)., (Copyright © 2024 Massachusetts Medical Society.)

Purpose: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor ( EGFR )-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy., Patients and Methods: Patients with EGFR -mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (C trough ; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUC D1-D15 ). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point., Results: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of C trough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUC D1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively., Conclusion: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

Background: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups., Patients and Methods: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR)., Results: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]., Conclusions: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti-PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti-PD-1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted and effector memory-like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti-PD-1 immunotherapy by pivoting T cell differentiation dynamics.

Introduction: Patients with oligometastatic NSCLC benefit from locally ablative therapies (LAT); the role of adjuvant systemic therapies, however, remains less clear. In a single-arm, phase II clinical trial, we found that patients with oligometastatic NSCLC treated with a year of pembrolizumab after LAT had superior progression-free survival (PFS) compared with a historical control cohort. Herein, we present long-term follow-up on PFS and overall survival (OS)., Methods: From February 1, 2015, to September 30, 2017, 45 patients with synchronous or metachronous oligometastatic (≤4 metastatic sites) NSCLC treated with LAT to all sites received adjuvant pembrolizumab every 21 days for up to 16 cycles. The primary efficacy end point was PFS from the start of pembrolizumab. Secondary end points included OS and safety. Median duration of follow-up was 66 months, and data cutoff was December 1, 2022., Results: A total of 45 patients were enrolled and treated with pembrolizumab after LAT (median age, 64 y [range, 46-82]; 21 women [47%]; 31 with a solitary oligometastatic site [69%]). At the data cutoff, 32 patients had progressive disease, 19 patients had died, and 13 patients had no evidence of relapse. Median PFS was 19.7 months (95% confidence interval: 7.6-31.7 mo); median OS was not reached (95% confidence interval: 37.7 mo-not reached). OS at 5 years was 60.0% (SE, 7.4%). Metachronous oligometastatic disease was associated with improved OS and PFS through Cox proportional hazard models., Conclusions: Pembrolizumab after LAT for oligometastatic NSCLC results in promising PFS and OS with a tolerable safety profile., Competing Interests: Dr. Cantor reports receiving honoraria from HMP. Dr. Aggarwal reports receiving institutional research funding from 10.13039/100004325AstraZeneca, 10.13039/100004328Genentech, 10.13039/100017655Incyte, 10.13039/100019794Macrogenics, 10.13039/501100004628Medimmune, and 10.13039/100009947Merck Sharp and Dohme, and receiving consultation fees from Genentech, Lilly, Celgene Merck, AstraZeneca, Blueprint Genetics, Shionogi, Daiichi Sankyo, Regeneron, Sanofi, Eisai, BeiGene, Turning Point, Pfizer, Janssen, and Boehringer Ingelheim. Dr. Evans reports receiving honoraria from Merck. Dr. Cohen reports receiving institutional research funding from F-Star Biotechnology, Innate Biopharma, and Cantargia. Dr. Bauml is currently employed by Janssen Research and Development but all work for this study was done as an employee at the University of Pennsylvania, and reports owning stock in Johnson & Johnson. Dr. Langer reports receiving institutional research funding from AstraZeneca, Eli Lilly, 10.13039/501100002424Fujifilm, 10.13039/100008897Janssen Pharmaceuticals, 10.13039/100016255Inovio, 10.13039/100004334Merck, Oncocyte, Takeda, and Trizell; receiving consulting fees from AstraZeneca, Boehringer Ingelheim, Genentech, Roche, Gilead, GlaxoSmithKline, Merck, Mirati, Novocure, Pfizer, Regeneron, Sanofi-Aventis, and Takeda; and having participation on a safety monitoring board or advisory board for Amgen, OncocyteDX, the Radiation Therapy Oncology Group Foundation, and the Veterans Administration. The remaining authors declare no conflict of interest., (© 2024 by the International Association for the Study of Lung Cancer.)

Background: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial., Patients and Methods: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion., Results: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy., Conclusions: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen., Competing Interests: Disclosure AP: consulting or advisory role for AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Lilly, GSK, Janssen, Merck Sharp & Dohme, Mundipharma, Novartis, and Roche; speakers bureaus for AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, eCancer, Janssen, Merck Sharp & Dohme, Medscape, PeerVoice, and touchONCOLOGY; steering committee member for Janssen and ArriVent Biopharma. SHL: received honoraria from AstraZeneca/MedImmune, Roche, Merck, Lilly, and Amgen; consulting or advisory role for AstraZeneca, Roche, Merck, Pfizer, and Lilly; received research funding from Merck. BM: received speaking honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Janssen, Jazz Pharmaceuticals, Merck, Novartis, Pfizer, Roche, Sanofi, and Takeda; received support for attending meetings from Janssen, Pfizer, and Sanofi. JYS: participated in advisory boards for AstraZeneca, Roche, Boehringer Ingelheim, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharmaceutical Co, Ono Pharmaceutical, Takeda, CStone Pharmaceuticals, Janssen, and Bristol Myers Squibb; received speaking honoraria from AstraZeneca, Roche, Boehringer Ingelheim, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharmaceutical Co, Ono Pharmaceutical, and Bristol Myers Squibb; received grant from Roche. KA: received lecture fees for AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Bristol Myers Squibb, and Chugai Pharmaceutical Co. OJV: honoraria or advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, AstraZeneca, Pfizer, Lilly, Takeda, and Janssen; received travel, accommodations, and expenses from Takeda, AstraZeneca, Merck Sharp & Dohme, Pfizer, and Roche/Genentech. EF: consulting or advisory role for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, GSK, Janssen, Merck Serono, Novartis, Pfizer, Sanofi, Takeda, Peptomyc, Daiichi Sankyo Europe GmbH, F. Hoffman La-Roche, Merck Sharp & Dohme, BerGenBio, and Turning Point Therapeutics; speakers bureaus for AstraZeneca, Bristol Myers Squibb, Lilly, Medscape, Merck Sharp & Dohme, PeerVoice, Pfizer, Takeda, Amgen, F. Hoffman La-Roche, Janssen, Medical Trends, Merck Serono, Sanofi, and touchONCOLOGY; other relationships with GRIFOLS; received research funding from Merck and Merck KgaA. NG: invited speaker for Amgen, AstraZeneca, Bristol Myers Squibb, Mirati Therapeutics, MSD, Novartis, Pfizer, Roche, and Sanofi; advisory roles for AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Grünenthal, Janssen, Lilly, MSD, Novartis, Owkin, Pfizer, Roche, Sanofi, and Takeda; received research funding for institution from Bristol Myers Squibb, Janssen, Roche, and Sivan; leadership role at ITMIG; family employment at AstraZeneca. ABC: invited speaker for Pfizer, Amgen, Takeda, Novartis, Roche, AstraZeneca, MSD, Janssen, Bristol Myers Squibb, and Sanofi; advisory roles for Novartis, AbbVie, Roche, Exeliom Biosciences, Pfizer, Janssen, Amgen, Takeda, AstraZeneca, and MSD; research funding of institution from Exeliom Biosciences; support for attending meetings from Roche, MSD, Novartis, Pfizer, AstraZeneca, Amgen, and Bristol Myers Squibb; participation on data monitoring safety board for InhaTarget Therapeutics and Merck. RC: invited speaker for Amgen, AstraZeneca, Lilly, GSK, Janssen, MSD, Pfizer, Roche, and Takeda; participated in advisory boards for Amgen, AstraZeneca, Bayer, Lilly, GSK, Janssen, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, and Takeda; speaker in educational activities for Medscape, PeerVoice, and TouchIME; holds stocks or shares in Supportive Care UK; has ownership interest in Christie Private Care; principal investigator for AbbVie, AstraZeneca, Bristol Myers Squibb, Clovis, Lilly, GSK, Janssen, MSD, Novartis, Pfizer, PharmaMar, Roche, and Takeda. FC: received consulting fees from Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Novocure, Mirati Therapeutics, Galecto, OSE Immunotherapeutics, and MSD; received honoraria for advisory role from Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Novocure, Mirati Therapeutics, Galecto, OSE Immunotherapeutics, and MSD; received support for attending meetings from OSE Immunotherapeutics; participated in advisory boards for Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Novocure, Mirati Therapeutics, Galecto, OSE Immunotherapeutics, and MSD. SO: received advisory board consulting fees from Janssen, Bristol Myers Squibb, Novocure, and Roche. SP: participated in advisory boards for Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GSK, Guardant Health, Janssen, Lilly, Medscape, MSD, Novartis, Pfizer, Sanofi, and Takeda; consulting fees from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; expert testimony for Merck Serono and Roche; invited speaker for VJOncology; received payment or honoraria from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, and Takeda; principal investigator for ARIAD Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Janssen, Lilly, Roche, Takeda, Trizel, and Turning Point Therapeutics; received support for attending meetings from Janssen and Roche; research grant from Guardant Health; other financial relationships with Amgen, Blueprint Medicines, Elsevier, and MSD. JLT: invited speaker for AstraZeneca, Lilly, MSD, Boehringer Ingelheim, Pfizer, and Takeda; participated in advisory boards for Amgen and AstraZeneca; received support for attending meetings from MSD. PT: received grants and nonfinancial support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Roche, and Takeda. RDG: received grants from Alliance Foundation, Amgen, AstraZeneca, Big Ten Cancer Research Consortium, Bristol Myers Squibb, Chugai Pharmaceutical Co, Daiichi Sankyo, ECOG-ACRIN, Helsinn, Hoosier Cancer Research Network, Janssen, Jounce Therapeutics, Merck, National Cancer Institute, Pfizer, and Takeda; received payment or honoraria from Clinical Care Options, OncLive, Society for Immunotherapy of Cancer, and Targeted Oncology; received support for attending meetings from the International Association for the Study of Lung Cancer; participated in advisory boards for AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Gilead, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Oncocyte, Sanofi, and Takeda; leadership or other role in ASCO Scientific Review Committee and Meeting Abstracts, Hoosier Cancer Research Network, Journal of Clinical Oncology, National Cancer Institute Investigational Drug Steering Committee, and the Thoracic Clinical Trial Working Group. WNWJr: participated in advisory boards for AstraZeneca, Bayer, Merck, Novartis, Sanofi, and Takeda; invited speaker for Amgen, Bristol Myers Squibb, Lilly, Genentech/Roche, Janssen, Pfizer, and United Medical; expert testimony for Boehringer Ingelheim. KR: consultant for Amgen, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, EMD Serono, Genentech, GSK, Janssen, Lilly, Merck KGA, Mirati Therapeutics, Seattle Genetics, and Takeda; writing assistance from Blueprint Medicines, Genentech, Janssen, Merck, Mirati Therapeutics, Seattle Genetics, and Takeda; research funding of institution from Genentech, Blueprint Medicines, Calithera, Daiichi Sankyo, Elevation Oncology, and Janssen. TT: received honoraria from AstraZeneca K.K., Pfizer Japan Inc, Eli Lilly Japan, Chugai Pharmaceutical Co, MSD K.K., Pfizer Japan Inc, Takeda, Bristol Myers Squibb Japan, Amgen K.K., and Novartis; research funding of institution from Janssen Pharmaceutical K.K., AstraZeneca K.K., Pfizer Japan Inc, Eli Lilly Japan, Chugai Pharmaceutical Co, MSD K.K., Amgen K.K., Merck Biopharma Co., Ltd., and AnHeart Therapeutics Inc. SG: principal investigator for AstraZeneca, Novartis, and Janssen (fees to institution). DMK: participated in advisory boards for MSD, Merck, Roche, Bristol Myers Squibb, Takeda, Boehringer Ingelheim, Pfizer, Johnson & Johnson, Amgen, Sanofi-Aventis, and Novartis. AB: received consulting fees from Pfizer and Roche; honoraria from Novartis and Eli Lilly; participated in advisory boards for Pfizer, Roche, and Regeneron. MM: received consulting fees from Boehringer Ingelheim, Roche, Takeda, and AstraZeneca. PB, ABB, AG, JG, DM, MW, JX, TS, SS, BD, REK, JMB: employee of Janssen and may hold stock in Johnson & Johnson. RGC: invited speaker for AstraZeneca, Bristol Myers Squibb, Janssen, Lilly, Novartis, Pfizer, Roche, and Takeda; advisory roles for AstraZeneca, Bristol Myers Squibb, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda; steering committee member for AstraZeneca and Janssen. BCC: consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Pfizer, Yuhan Corporation, Janssen, Takeda, Merck Sharp & Dohme, Ono Pharmaceutical, Lilly, MedPacto, Blueprint Medicines, Cyrus Therapeutics, Guardant Health, Novartis, CJ, ABION, BeiGene, CureLogen, Onegene Biotechnology, GI-Cell, HK inno.N, IMNEWRUN, Hanmi Pharmaceutical, Kanaph Therapeutics, BridgeBio, and Oscotec; leadership roles for Interpark Bio and J INTS BIO; patents, royalties, or other intellectual property for Champions Oncology, Crown Bioscience, and Imagen; other relationships with DAAN Biotherapeutics; owns stock or has other ownership interests with Theravance Biopharma, Gencurix, BridgeBio, Kanaph Therapeutics, Cyrus Therapeutics, Interpark Bio, and J INTS BIO; received research funding from Novartis, Bayer, AstraZeneca, MOGAM Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan Corporation, Ono Pharmaceutical, Dizal Pharma, Merck Sharp & Dohme, AbbVie, GI Innovation, Lilly, Blueprint Medicines, Interpark Bio, LG Chem, Oscotec, GI-Cell, ABION, Boehringer Ingelheim, CJ Bioscience, CJ Blossom Park, Cyrus Therapeutics, Genexine, Nuvalent Inc, Oncternal Therapeutics, Regeneron, BridgeBio, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, J INTS Bio, Hanmi Pharmaceutical, and CHA Bundang Medical Center. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR-mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival and overall survival. The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified. In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed overall response rate was 36% (95% confidence interval, 22-51). The median duration of response was 9.6 months, and the median progression-free survival was 4.9 months. Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 ., (© 2023. The Author(s).)

Background: In RAS-mutant tumors, combined MEK and autophagy inhibition using chloroquine demonstrated synthetic lethality in preclinical studies. This phase II trial evaluated the safety and activity of the MEK inhibitor binimetinib combined with hydroxychloroquine (HCQ) in patients with advanced KRAS-mutant non-small cell lung cancer (NSCLC)., Methods: Eligibility criteria included KRAS-mutant NSCLC, progression after first-line therapy, ECOG PS 0-1, and adequate end-organ function. Binimetinib 45 mg was administered orally (p.o.) bid with HCQ 400 mg p.o. bid. The primary endpoint was objective response rate (ORR). A Simon's 2-stage phase II clinical trial design was used, with an α error of 5% and a power β of 80%, anticipating an ORR of 30% to proceed to the 2-stage expansion., Results: Between April 2021 and January 2022, 9 patients were enrolled to stage I: median age 64 years, 44.4% females, 78% smokers. The best response was stable disease in one patient (11.1%). The median progression free survival (PFS) was 1.9 months, and median overall survival (OS) was 5.3 months. Overall, 5 patients (55.6%) developed a grade 3 adverse event (AE). The most common grade 3 toxicity was rash (33%). Pre-specified criteria for stopping the trial early due to lack of efficacy were met., Conclusion: The combination of B + HCQ in second- or later-line treatment of patients with advanced KRAS-mutant NSCLC did not show significant antitumor activity. (ClinicalTrials.gov Identifier: NCT04735068)., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Amivantamab, a fully humanized EGFR-MET bispecific antibody, has antitumor activity in diverse EGFR- and MET-driven non-small cell lung cancer (NSCLC) and a safety profile consistent with associated on-target activities. Infusion-related reaction(s) (IRR[s]) are reported commonly with amivantamab. We review IRR and subsequent management in amivantamab-treated patients., Methods: Patients treated with the approved dose of intravenous amivantamab (1050 mg, <80 kg; 1400 mg, ≥80 kg) in CHRYSALIS-an ongoing, phase 1 study in advanced EGFR-mutated NSCLC-were included in this analysis. IRR mitigations included split first dose (350 mg, day 1 [D1]; remainder, D2), reduced initial infusion rates with proactive infusion interruption, and steroid premedication before initial dose. For all doses, pre-infusion antihistamines and antipyretics were required. Steroids were optional after the initial dose., Results: As of 3/30/2021, 380 patients received amivantamab. IRRs were reported in 256 (67%) patients. Signs/symptoms of IRR included chills, dyspnea, flushing, nausea, chest discomfort, and vomiting. Most of the 279 IRRs were grade 1 or 2; grade 3 and 4 IRR occurred in 7 and 1 patients, respectively. Most (90%) IRRs occurred on cycle 1, D1 (C1D1); median time-to-first-IRR onset during C1D1 was 60 min; and first-infusion IRRs did not compromise subsequent infusions. Per protocol, IRR was mitigated on C1D1 with holding of infusion (56% [214/380]), reinitiating at reduced rate (53% [202/380]), and aborting infusion (14% [53/380]). C1D2 infusions were completed in 85% (45/53) of patients who had C1D1 infusions aborted. Four patients (1% [4/380]) discontinued treatment due to IRR. In studies aimed at elucidating the underlying mechanism(s) of IRR, no pattern was observed between patients with versus without IRR., Conclusion: IRRs with amivantamab were predominantly low grade and limited to first infusion, and rarely occurred with subsequent dosing. Close monitoring for IRR with the initial amivantamab dose and early intervention at first IRR signs/symptoms should be part of routine amivantamab administration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Janssen Research and Development LLC. Published by Elsevier B.V. All rights reserved.)

Background: We performed an integrated biomarker evaluation in pembrolizumab-treated patients with R/M HNSCC enrolled in KEYNOTE-012 or KEYNOTE-055. The relationship between biomarkers and HPV status was explored., Methods: We evaluated PD-L1 (combined positive score [CPS]), TMB, T-cell-inflamed gene expression profile (Tcell inf GEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS)., Results: Two hundred and fifty-seven patients (KEYNOTE-012, n = 106; KEYNOTE-055, n = 151) had TMB data available; of these, 254 had PD-L1 and 236 had Tcell inf GEP. TMB, PD-L1, and Tcell inf GEP were each significantly associated with ORR (p < 0.01). Kaplan-Meier curves at prespecified cutoffs generally showed PFS and OS separation in the anticipated direction for these biomarkers, except for OS and TMB. TMB did not correlate with PD-L1 or Tcell inf GEP (Spearman ρ = -0.03 and ρ = -0.13, respectively); PD-L1 and Tcell inf GEP were moderately correlated (Spearman ρ = 0.47). In multivariate models, TMB, PD-L1, and Tcell inf GEP were each independently predictive for ORR (p < 0.001). ORR was higher in patients with high versus low levels of biomarkers when dichotomized using prespecified cutoffs; patients with higher versus lower levels of TMB and PD-L1 or TMB and Tcell inf GEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD-L1, TMB, and Tcell inf GEP) were associated with response. HPV detection by p16-immunohistochemistry and WES showed good concordance (81%); results were generally similar by HPV status, regardless of the detection method., Conclusions: TMB and the inflammatory biomarkers PD-L1 and Tcell inf GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) account for ≤ 12% of all EGFR-mutant nonsmall cell lung cancers. We analysed real-world datasets to determine the frequency of ex20ins variants, and the ability of polymerase chain reaction (PCR) and next-generation sequencing (NGS) to identify them. Three real-world United States NGS databases were used: GENIE, FoundationInsights, and GuardantINFORM. Mutation profiles consistent with in-frame EGFR ex20ins were summarized. GENIE, FoundationInsights, and GuardantINFORM datasets identified 180, 627, and 627 patients with EGFR ex20ins respectively. The most frequent insertion region of exon 20 was the near loop (~ 70%), followed by the far loop (~ 30%) and the helical (~ 3-6%) regions. GENIE, FoundationInsights, and GuardantINFORM datasets identified 41, 102, and 96 unique variants respectively. An analysis of variants projected that ~ 50% of EGFR ex20ins identified by NGS would have been missed by PCR-based assays. Given the breadth of EGFR ex20ins identified in the real-world US datasets, the ability of PCR to identify these mutations is limited. NGS platforms are more appropriate to identify patients likely to benefit from EGFR ex20ins-targeted therapies., (© 2022 Janssen Global Services, LLC. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Percutaneous endoscopic gastronomy (PEG) tubes are commonly used to administer enteral nutrition during head and neck cancer (HNC) treatment. However, the benefits of placing a prophylactic feeding tube (PFT; prior to radiotherapy [RT]) or reactive feeding tube (RFT, after RT initiation) are unclear. We sought to compare survival, body mass trends, and hospitalization rates between strategies., Methods: We conducted a retrospective cohort study of 11,473 Veterans with stages III-IVC HNC treated with chemoradiotherapy. Patients with PEG tube placement within 30 days prior to treatment initiation (PFT) were compared to all other patients (non-PFT) or patients with PEG tube placement within 3 months after treatment initiation placement (RFT). We compared survival, longitudinal body mass changes, and hospitalization rates for PFT versus non-PFT or RFT patients in propensity score (PS)-matched Cox regression models., Results: 3,186 (28 %) patients received PFT and 8,287 (72 %) were non-PFT, of which 1,874 (23 %) received RFT. After PS-matching, there were no significant differences in overall survival (HR 0.97, 95 % CI 0.92-1.02), HNC-specific survival (HR 0.98, 95 % CI 0.92-1.09), change in BMI (p = 0.24), or hospitalization rates between PFT and non-PFT groups. Significant differences in hospitalization rates between PFT and RFT groups persisted after PS-matching (-0.11 hospitalizations/month), but no differences were found for other outcomes., Conclusion: Timing of PEG tube placement in Veterans with HNC was not associated with any significant survival or body mass advantage. However, patients who received PFT had a lower hospitalization rate than those who received RFT., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joshua M. Bauml reports a consulting/advisory role with Clovis Oncology, Bristol-Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, Janssen, Takeda, Ayala, Regeneron, Inivata, Foundation Medicine, Novartis, and Guardant Health; Bauml also reports research support provided to his institution for other projects by Merck, Janssen, Carevive Systems, Novartis, Clovis Oncology, AstraZeneca, Takeda, and Bayer. All other authors declare no conflict of interest regarding the publication of this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: The activity of immune checkpoint inhibitors (ICIs) in NSCLC harboring EGFR exon 20 insertion mutations (ex20ins) has not been closely examined due to the frequent exclusion of patients with EGFR mutations from large immunotherapy-based NSCLC trials., Patients and Methods: A real-world, retrospective study was conducted to compare outcomes of ICI-treated patients with EGFR ex20ins and wildtype NSCLC (wt-NSCLC; defined as EGFR and ALK test negative). Patients with advanced NSCLC from the Flatiron Health database (2015-2020) were included in the analysis. Real-world time to next therapy (rwTTNT) and overall survival (rwOS), stratified by ICI initiation line of therapy, were the prespecified primary and secondary endpoints, respectively., Results: Among 59 patients with EGFR ex20ins NSCLC and 5365 with wt-NSCLC, ICI treatment was received as first-line therapy in 25% and 39%, respectively. Patients with EGFR ex20ins had a 58% increased risk of shorter time to next-line therapy compared with wt-NSCLC (adjusted hazard ratio of 1.58 [95% confidence interval [CI], 1.2-2.1]; P = .0012). The median rwTTNT for first ICI line was 3.7 months (95% CI, 3.0-4.9) for EGFR ex20ins NSCLC compared with 5.8 months (95% CI, 5.6-6.0) for wt-NSCLC. No meaningful difference in rwOS between the groups was observed., Conclusions: ICI therapy may be less effective for patients with EGFR ex20ins compared with wt-NSCLC. Consistent with prior data on exon 19 deletion and L858R substitution, tumors harboring ex20ins appear to be less responsive to immune checkpoint inhibition than wt-NSCLC., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

We aim to determine the feasibility of a novel radiomic biomarker that can integrate with other established clinical prognostic factors to predict progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) undergoing first-line immunotherapy. Our study includes 107 patients with stage 4 NSCLC treated with pembrolizumab-based therapy (monotherapy: 30%, combination chemotherapy: 70%). The ITK-SNAP software was used for 3D tumor volume segmentation from pre-therapy CT scans. Radiomic features (n = 102) were extracted using the CaPTk software. Impact of heterogeneity introduced by image physical dimensions (voxel spacing parameters) and acquisition parameters (contrast enhancement and CT reconstruction kernel) was mitigated by resampling the images to the minimum voxel spacing parameters and harmonization by a nested ComBat technique. This technique was initialized with radiomic features, clinical factors of age, sex, race, PD-L1 expression, ECOG status, body mass index (BMI), smoking status, recurrence event and months of progression-free survival, and image acquisition parameters as batch variables. Two phenotypes were identified using unsupervised hierarchical clustering of harmonized features. Prognostic factors, including PDL1 expression, ECOG status, BMI and smoking status, were combined with radiomic phenotypes in Cox regression models of PFS and Kaplan Meier (KM) curve-fitting. Cox model based on clinical factors had a c-statistic of 0.57, which increased to 0.63 upon addition of phenotypes derived from harmonized features. There were statistically significant differences in survival outcomes stratified by clinical covariates, as measured by the log-rank test (p = 0.034), which improved upon addition of phenotypes (p = 0.00022). We found that mitigation of heterogeneity by image resampling and nested ComBat harmonization improves prognostic value of phenotypes, resulting in better prediction of PFS when added to other prognostic variables., (© 2022. The Author(s).)

Background: Better therapies are needed to improve survival in metastatic non-small cell lung cancer (NSCLC). Given the synergy of combination nab-paclitaxel and gemcitabine in metastatic pancreatic cancer and their individual activity in advanced NSCLC, we sought to determine whether the same combination would confer a therapeutic benefit in the second-line therapy of recurrent or metastatic non-squamous (NSQ) NSCLC., Materials and Methods: This single-arm phase II trial of nab-paclitaxel and gemcitabine was performed from June 2015 to April 2020 at an academic referral cancer center. Patients with advanced NSQ-NSCLC whose disease progressed on first-line pemetrexed plus platinum +/- immunotherapy were enrolled. Patients received intravenous nab-paclitaxel 100 mg/m 2 and gemcitabine 1000 mg/m 2 on days 1 and 8 of each 21-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety and tolerability were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0., Results: Thirty-seven patients (15 men [41%] and 22 women [59%]; median age, 66 years [range, 41-81 years]) were accrued. ORR was 13.5% (95% CI, 2.5-24.5%). DCR was 59.5% (95% CI, 43.5-75.5%). Median PFS was 2.6 months (95% CI, 1.4-3.8 months). Median OS was 6.2 months (95% CI, 4.2-8.2 months). 1-year OS was 24% (95% CI, 10-38%). Safety and tolerability were similar to other second-line chemotherapies, although there was an 11% incidence of grade 2-3 pneumonitis., Conclusion: Combination nab-paclitaxel and gemcitabine after platinum and pemetrexed for NSQ-NSCLC was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting. The higher-than-expected risk of pneumonitis was also concerning., Trial Registration: ClinicalTrials.gov Identifier: NCT02303977 MICRO-ABSTRACT: In this phase II trial, 37 patients with metastatic non-squamous non-small cell lung cancer were treated with nab-paclitaxel/gemcitabine in second-line. ORR = 13.5% (95% CI, 2.5%-24.5%). Median PFS = 2.6 months (95% CI, 1.4-3.8 months). Median OS = 6.2 months (95% CI, 4.2-8.2 months). Nab-paclitaxel and gemcitabine was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: In the single-arm CHRYSALIS study, amivantamab showed durable responses and manageable safety in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) who progressed on prior platinum-based chemotherapy. External controls can provide context for interpreting amivantamab efficacy., Methods: External controls were selected from three US-based databases (ConcertAI, COTA, and Flatiron). Key inclusion criteria were diagnosis of EGFR ex20ins advanced NSCLC, prior platinum-based chemotherapy, and performance status score ≤ 1. Duplicate external controls were identified using a tokenization procedure and removed, and adjustment for differences in baseline characteristics between amivantamab-treated and external control cohorts was achieved using propensity score weighting., Results: Amivantamab-treated and pooled external control cohorts included 81 and 125 patients, respectively. Baseline characteristics were generally similar across cohorts, except more amivantamab-treated patients were Asian (56% vs 13%). Most common therapies received by external controls were non-platinum-based chemotherapy (25.1%), immuno-oncology therapies (24.2%), EGFR tyrosine kinase inhibitors (16.3%), and platinum-based chemotherapy (16.3%). Overall response rate was 40% among amivantamab-treated patients and 16% among external controls. Amivantamab-treated patients had longer progression-free survival (median 8.3 vs 2.9 months; hazard ratio [HR; 95% CI]: 0.47 [0.34-0.65]), time to next therapy (median 14.8 vs 4.8 months; HR [95% CI]: 0.40 [0.28-0.57]), and overall survival (median 22.8 vs 12.8 months; HR [95% CI]: 0.49 [0.31-0.77]) than external controls. Results were consistent in sensitivity analyses comparing each external control dataset against the amivantamab-treated group separately., Conclusion: Among post-platinum patients with EGFR ex20ins advanced NSCLC, those treated with amivantamab had improved outcomes, including 10-month longer overall survival, versus external controls., (Copyright © 2022 Janssen Research and Development LLC. Published by Elsevier B.V. All rights reserved.)

Background: Overall survival for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) has differed by sex, but little is known regarding cancer-specific outcomes. We assessed the independent association of sex with cancer-specific survival in patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC)., Methods: We identified 14,183 patients from the Surveillance, Epidemiology, and End Results (SEER) program with OPSCC and tumor HPV status. We used Kaplan-Meier methods to compare overall survival (OS) and OPSCC-specific survival (HNCSS) by patient sex and by tumor HPV status. We then separately fit multivariable survival and competing risk models evaluating the association of sex on these outcomes by tumor HPV status and stratified by the use of guideline-concordant OPSCC treatment., Results: A total of 10,210 persons with HPV-positive tumors (72.0%) and 3,973 with HPV-negative tumors (28.0%) were identified. A larger proportion of women had HPV-negative tumors (24.0%) versus HPV-positive tumors (13.2%; p < 0.001). Women with HPV-positive tumors were less likely to receive guideline-concordant treatment compared to men. In unadjusted survival analyses, women did not differ in OS or HNCSS compared to men for HPV-positive tumors but had worse OS and HNCSS for HPV-negative tumors. After adjustment, men and women with HPV-positive OPSCC did not differ in OS or HNCSS. However, women with HPV-negative tumors faced worse overall survival (hazard ratio (HR) 1.15, 95% CI 1.02-1.29) that persisted even after stratifying for stage-appropriate treatment (HR 1.28, 95% CI 1.11-1.47)., Conclusions: Women with HPV-positive OPSCC had similar survival outcomes compared to men, but those with HPV-negative tumors have worse overall and cancer-specific survival., Competing Interests: Joshua M. Bauml reports a consulting/advisory role with Clovis Oncology, Bristol-Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, Janssen, Takeda, Ayala, Regeneron, Inivata, Foundation Medicine, Novartis, and Guardant Health; Bauml also reports research support provided to his institution for other projects by Merck, Janssen, Carevive Systems, Novartis, Clovis Oncology, AstraZeneca, Takeda, and Bayer. All other authors declare no conflict of interest regarding the publication of this article., (Copyright © 2022 Derek D. Kao et al.)

Introduction: This multicenter review evaluated the efficacy and safety of osimertinib dose escalation for central nervous system (CNS) progression developing on osimertinib 80 mg in EGFR -mutant NSCLC., Methods: Retrospective review identified 105 patients from eight institutions with advanced EGFR -mutant NSCLC treated with osimertinib 160 mg daily between October 2013 and January 2020. Radiographic responses were clinically assessed, and Kaplan-Meier analyses were used. We defined CNS disease control as the interval from osimertinib 160 mg initiation to CNS progression or discontinuation of osimertinib 160 mg., Results: Among 105 patients treated with osimertinib 160 mg, 69 were escalated for CNS progression, including 24 treated with dose escalation alone (cohort A), 34 who received dose-escalated osimertinib plus concurrent chemotherapy and/or radiation (cohort B), and 11 who received osimertinib 160 mg without any prior 80 mg exposure. The median duration of CNS control was 3.8 months (95% confidence interval [CI], 1.7-5.8) in cohort A, 5.1 months (95% CI, 3.1-6.5) in cohort B, and 4.2 months (95% CI 1.6-not reached) in cohort C. Across all cohorts, the median duration of CNS control was 6.0 months (95% CI, 5.1-9.0) in isolated leptomeningeal progression (n = 27) and 3.3 months (95% CI, 1.0-3.1) among those with parenchymal-only metastases (n = 23). Patients on osimertinib 160 mg experienced no severe or unexpected side effects., Conclusion: Among patients with EGFR -mutant NSCLC experiencing CNS progression on osimertinib 80 mg daily, dose escalation to 160 mg provided modest benefit with CNS control lasting approximately 3 to 6 months and seemed more effective in patients with isolated leptomeningeal CNS progression., (© 2022 The Authors.)

Objectives: Effective therapy for non-small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation., Materials and Methods: KRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. Matched tissue and plasma samples were procured from other clinical trials or commercial vendors, and results were compared. Demographics and clinical characteristics and objective response rate (ORR) were evaluated., Results: Of 126 CodeBreaK patients, 112 (88.9%) were tested for KRASp.G12C mutations with Guardant360 CDx. Among 189 patients in the extended analysis cohort, the positive and negative percent agreement (95% CI) for Guardant360 CDx plasma testing relative to therascreen® KRAS RGQ PCR kit tissue testing were 0.71 (0.62, 0.79) and 1.00 (0.95, 1.00), respectively; overall percent agreement (95% CI) was 0.82 (0.76, 0.87). TP53 co-mutations were the most common regardless of KRAS p.G12C status (KRAS p.G12C-positive, 53.4%; KRAS p.G12C-negative, 45.5%). STK11 was co-mutated in 26.1% of KRAS p.G12C-positive samples. The ORR was similar among patients selected by plasma and tissue testing., Conclusion: Comprehensive genotyping for all therapeutic targets including KRAS p.G12C is critical for management of NSCLC. Liquid biopsy using Guardant360 CDx has clinical validity for identification of patients with KRASp.G12C-mutant NSCLC and, augmented by tissue testing methodologies as outlined on the approved product label, will identify patients for treatment with sotorasib., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: The availability of targeted therapies has transformed the management of advanced NSCLC; however, most patients do not undergo guideline-recommended tumor genotyping. The impact of plasma-based next-generation sequencing (NGS) performed simultaneously with diagnostic biopsy in suspected advanced NSCLC has largely been unexplored., Methods: We performed a prospective cohort study of patients with suspected advanced lung cancer on the basis of cross-sectional imaging results. Blood from the time of biopsy was sequenced using a commercially available 74-gene panel. The primary outcome measure was time to first-line systemic treatment compared with a retrospective cohort of consecutive patients with advanced NSCLC with reflex tissue NGS., Results: We analyzed the NGS results from 110 patients with newly diagnosed advanced NSCLC: cohorts 1 and 2 included 55 patients each and were well balanced regarding baseline demographics. In cohort 1, plasma NGS identified therapeutically informative driver mutations in 32 patients (58%) (13 KRAS [five KRAS G12C ], 13 EGFR , two ERRB2 , two MET , one BRAF , one RET ). The NGS results were available before the first oncology visit in 85% of cohort 1 versus 9% in cohort 2 ( p < 0.0001), with more cohort 1 patients receiving a guideline-concordant treatment recommendation at this visit (74% versus 46%, p  = 0.005). Time-to-treatment was significantly shorter in cohort 1 compared with cohort 2 (12 versus 20 d, p  = 0.003), with a shorter time-to-treatment in patients with specific driver mutations (10 versus 19 d, p  = 0.001)., Conclusions: Plasma-based NGS performed at the time of diagnostic biopsy in patients with suspected advanced NSCLC is associated with decreased time-to-treatment compared with usual care., (© 2022 The Authors.)

Objectives: Sex differences in surgically treated HPV-associated oropharyngeal squamous cell carcinoma are not defined due to the low number of affected women. We explored the oncologic outcomes of men and women with p16-positive oropharyngeal squamous cell carinoma treated with primary surgery., Materials and Methods: Retrospective analysis of patients with HPV-related oropharyngeal cancer treated with surgery and pathology guided adjuvant therapy from 2007 to 2017. Primary end point was recurrence-free and overall survival., Results: Of 468 men (86.7%) and 72 women (13.3%), women presented more often with clinical N0 nodal disease (25% vs 12.2%). There were no differences in adverse pathologic features or T stage, although women were more likely to present with N0 disease (16.7% vs 10%), less N2 disease (6.9% vs 17.7%, p = 0.03), and more stage I disease (88.9% vs 75%). As a result, women were more likely to undergo surgery alone (30.6% vs 14.1%) while men were more likely to require adjuvant radiation therapy (47.2% vs 36.1%). Four women (5.6%) and 30 men (6.4%, p = 0.8) died during follow-up. Multivariate analysis controlling for age, sex, treatment, and pathologic stage demonstrated no differences in overall survival between men and women. There were no differences in recurrence-free or overall survival between men and women at two and five years., Conclusions: Although women undergoing transoral robotic surgery for HPV+ oropharyngeal squamous cell carcinoma may have less advanced disease, upfront surgery with pathology-guided adjuvant therapy produces similar oncologic results in men and women while accounting for disease burden., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To analyze the patterns, risk factors, and salvage outcomes for locoregional recurrences (LRR) after treatment with transoral robotic surgery (TORS) for HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC)., Study Design: Retrospective analysis of HPV+ OPSCC patients completing primary TORS, neck dissection, and NCCN-guideline-compliant adjuvant therapy at a single institution from 2007 to 2017., Methods: Features associated with LRR, detailed patterns of LRR, and outcomes of salvage therapy were analyzed. Disease-free survival (DFS) and overall survival (OS) were calculated for subgroups of patients receiving distinct adjuvant treatments., Results: Of 541 patients who completed guideline-indicated therapy, the estimated 5-year LRR rate was 4.5%. There were no identifiable clinical or pathologic features associated with LRR. Compared to patients not receiving adjuvant therapy, those who received indicated adjuvant radiation alone had a lower risk of LRR (HR 0.28, 95% CI [0.09-0.83], P = .023), but there was no difference in DFS (P = .21) and OS (P = .86) between adjuvant therapy groups. The 5-year OS for patients who developed LRR was 67.1% vs. 93.9% for those without LRR (P < .001). Patients who initially received adjuvant chemoradiation and those suffering local, in-field, and/or retropharyngeal node recurrences had decreased disease control after salvage therapy., Conclusion: LRR rates are low for HPV+ OPSCCs completing TORS and guideline-compliant adjuvant therapy. Patients without indication for adjuvant therapy more often suffer LRR, but these recurrences are generally controllable by salvage therapy. Improved understanding of the patterns of recurrence most amenable to salvage therapy may guide treatment decisions, counseling, and adjuvant therapy de-escalation trials., Level of Evidence: 3 Laryngoscope, 131:E2865-E2873, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction: Real-world clinical outcomes in patients with advanced NSCLC harboring EGFR exon 20 insertion (exon20ins) mutations have not been extensively studied. We conducted a retrospective cohort study to assess the clinical outcomes of EGFR exon20ins compared with common EGFR (cEGFR) mutations., Methods: Adults with advanced NSCLC harboring any EGFR mutations in the NSCLC Flatiron registry (2011 through May 2020) were included. To compare the relative prognosis (prognostic value) of exon20ins vs cEGFR, real-world overall survival (rwOS) was the primary endpoint. Separately, to compare the relative response to tyrosine kinase inhibitor (TKI) treatment (predictive value), real-world progression-free survival (rwPFS) was the primary endpoint., Results: For the prognostic value analysis, 3014 patients with EGFR mutant NSCLC (cEGFR, n = 2833; EGFR exon20ins, n = 181) were eligible. The median (95% CI) rwOS was 16.2 (11.04-19.38) months in the EGFR exon20ins cohort vs 25.5 (24.48-27.04) months in the cEGFR cohort (adjusted HR, 1.75 [1.45-2.13]; p < 0.0001); 5-year rwOS was 8% and 19%, respectively. For the predictive value analysis, 2825 patients received TKI treatment and were eligible (cEGFR, n = 2749; EGFR exon20ins, n = 76). The median (95% CI) rwPFS from start of the first TKI was 2.9 (2.14-3.91) months in the EGFR exon20ins cohort vs 10.5 (10.05-10.94) months in the cEGFR cohort (adjusted HR, 2.69 [2.05-3.54]; p < 0001). Among patients with EGFR exon20ins, the most common prescribed first-line therapy was platinum-based chemotherapy (61.3%) followed by EGFR TKIs (21.5%); second-line treatments were varied, with no clear standard of care., Conclusions: Patients with EGFR exon20ins have poor prognosis and receive little benefit from EGFR TKI treatment. More effective therapies are needed in this difficult-to-treat population., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site., Methods: CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with EGFR Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum EGFR Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5., Results: In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively., Conclusion: Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with EGFR Exon20ins mutations after progression on platinum-based chemotherapy., Competing Interests: Keunchil ParkConsulting or Advisory Role: AstraZeneca, Lilly, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Blueprint Medicines, Amgen, Merck KGaA, LOXO, AbbVie, Daiichi Sankyo, Boehringer Ingelheim, JNJ, Eisai, Puma BiotechnologySpeakers' Bureau: Boehringer IngelheimResearch Funding: AstraZeneca, MSD Oncology Eric B. HauraConsulting or Advisory Role: Janssen Oncology, Revolution Medicines, Ellipses Pharma, Janssen Research & Development, AmgenResearch Funding: Janssen, Novartis, Revolution Medicines, AstraZeneca, Incyte, Genentech, Spectrum PharmaceuticalsPatents, Royalties, Other Intellectual Property: Protein-Protein Interactions as Biomarkers Patent Natasha LeighlHonoraria: Boehringer IngelheimConsulting or Advisory Role: XcoveryResearch Funding: Novartis, Roche Canada, Guardant Health, MSD, EMD Serono, LillyTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bristol Myers Squibb, Nektar, GlaxoSmithKline, Roche, AstraZeneca Paul MitchellHonoraria: MSD, AstraZeneca, RocheConsulting or Advisory Role: Roche, Specialised Therapeutics, PUMA Biotechnology, AstraZeneca, Boehringer Ingelheim, BMS, MSD, Amgen Catherine A. ShuConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Genentech/RocheResearch Funding: Celgene, Genentech/Roche, Janssen, MedImmuneTravel, Accommodations, Expenses: Genentech/Roche Nicolas GirardEmployment: AstraZenecaConsulting or Advisory Role: Roche, Lilly, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Bristol Myers Squibb, MSD, Takeda, GlaxoSmithKline, AbbVie, Pharmamar, Janssen, SanofiResearch Funding: Roche, AstraZeneca, Boehringer IngelheimTravel, Accommodations, Expenses: Roche, AstraZeneca, Bristol Myers Squibb, MSD Oncology Santiago ViteriConsulting or Advisory Role: Roche, Bristol Myers Squibb, Janssen, Takeda, Reddy Pharma Iberia, Merck KGaASpeakers' Bureau: Bristol Myers Squibb, RocheTravel, Accommodations, Expenses: Roche, MSD, Merck KGaA Ji-Youn HanHonoraria: Roche, AstraZeneca, Bristol Myers Squibb, TakedaConsulting or Advisory Role: MSD Oncology, AstraZeneca, Bristol Myers Squibb, Lilly, Novartis, Takeda, PfizerResearch Funding: Roche, Pfizer, Ono Pharmaceutical, Takeda Chee Khoon LeeHonoraria: AstraZeneca, Pfizer, Amgen, Takeda, Yuhan, Boehringer IngelheimConsulting or Advisory Role: Novartis, Boehringer Ingelheim, Takeda, AstraZeneca, Yuhan, AmgenResearch Funding: AstraZeneca, Roche, Merck KGaA Joshua K. SabariConsulting or Advisory Role: AstraZeneca, Janssen Oncology, Navire, Pfizer, Regeneron, Medscape, Takeda Alexander I. SpiraStock and Other Ownership Interests: LillyHonoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, BayerConsulting or Advisory Role: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Merck, Bristol Myers SquibbResearch Funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, LAM Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone Oncology, Plexxikon, Amgen, Loxo, Daiichi Sankyo, ADC Therapeutics, Janssen Oncology, Mirati Therapeutics, Rubius Therapeutics Dong-Wan KimResearch Funding: Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Boehringer Ingelheim, Amgen, Daiichi Sankyo, Chong Kun Dang Pharmaceutical, BridgeBio Pharma, GlaxoSmithKlineTravel, Accommodations, Expenses: Daiichi Sankyo, Amgen Ki Hyeong LeeConsulting or Advisory Role: Bristol Myers Squibb, MSD, AstraZeneca, Pfizer, Lilly Rachel E. SanbornHonoraria: AstraZeneca, AmgenConsulting or Advisory Role: Genentech/Roche, AstraZeneca, EMD Serono, Blueprint Medicines, Daiichi Sankyo/Lilly, Janssen Oncology, MacrogenicsResearch Funding: Bristol Myers Squibb, MedImmune, Merck, AstraZenecaTravel, Accommodations, Expenses: AstraZeneca José TrigoConsulting or Advisory Role: Takeda, Boehringer Ingelheim, Bristol Myers Squibb, Merck SeronoSpeakers' Bureau: MSD Oncology, AstraZeneca, Merck Serono, RocheTravel, Accommodations, Expenses: MSD Oncology, Bristol Myers Squibb, AstraZeneca Koichi GotoHonoraria: Guardant Health, Janssen, Daiichi Sankyo Co Ltd, Amgen, Eisai, Kyowa Kirin Co Ltd, Bristol Myers Squibb, AstraZeneca Japan, Pfizer, Chugai Pharma, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, Lilly Japan, Boehringer Ingelheim, Life Technologies, MSD K.K, Nippon Kayaku, Takeda, OtsukaConsulting or Advisory Role: OtsukaResearch Funding: Medical & Biological Laboratories Co Ltd, Kyowa Kirin Co Ltd, Amgen Astellas BioPharma, Kissei Pharmaceutical, Merck, Merus, NEC Corporation, Spectrum Pharmaceuticals, Shanghai HaiHe Pharmaceutical, MSD K.K, AstraZeneca Japan, Taiho Pharmaceutical, Chugai Pharma, Boehringer Ingelheim, Ono Pharmaceutical, Sumitomo Dainippon Pharma Co Ltd, Takeda, Astellas Pharma, Eisai, Lilly Japan, Pfizer, Bristol Myers Squibb, Ignyta, Life Technologies, Janssen, Xcoo, Loxo, Sysmex, Amgen James Chih-Hsin YangHonoraria: Boehringer Ingelheim, Roche, MSD, AstraZeneca, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Lilly, PfizerConsulting or Advisory Role: Boehringer Ingelheim, Novartis, AstraZeneca, Clovis Oncology, Lilly, MSD Oncology, Merck Serono, Celgene, Bayer, Pfizer, Ono Pharmaceutical, Bristol Myers Squibb, Yuhan, Hansoh, Blueprint Medicines, Daiichi Sankyo, G1 Therapeutics, AbbVie, Takeda Oncology, Amgen, Incyte, Merck Serono, Jenssen, GSK, Takeda, Daiichi Sankyo, NovartisTravel, Accommodations, Expenses: Pfizer Ramaswamy GovindanHonoraria: Genentech/AbbVie, AbbVie, Geneplus-Beijing InstituteConsulting or Advisory Role: Genentech/Roche, AbbVie, AstraZeneca/MedImmune, Pfizer, Bristol Myers Squibb, Nektar, Jounce Therapeutics, F. Hoffmann La Roche AG, Janssen, Amgen, Achilles Therapeutics Joshua M. BaumlConsulting or Advisory Role: Bristol Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, Guardant Health, Takeda, Novartis, Janssen, Ayala Pharmaceuticals, Regeneron, Inivata, Novartis, Foundation MedicineResearch Funding: Merck, Carevive Systems, Novartis, Incyte, Bayer, Janssen, AstraZeneca, Takeda, Amgen, Pfizer, Mirati Therapeutics Pilar GarridoConsulting or Advisory Role: Roche Pharma AG, AstraZeneca, MSD Oncology, Bristol Myers Squibb, Takeda, Lilly, Pfizer, Novartis/Pfizer, Boehringer Ingelheim, AbbVie, Amgen, Bayer, Gebro Pharma, Nordic Group, Boehringer Ingelheim, Janssen Biotech, Janssen Oncology, GlaxoSmithKlineSpeakers' Bureau: Roche Pharma AG, Takeda, AstraZeneca, MSD Oncology, BMS, Pfizer, Novartis, Boehringer Ingelheim, Nordic Group, Janssen, Boehringer Ingelheim, Janssen OncologyTravel, Accommodations, Expenses: AstraZeneca, Roche, Bristol Myers SquibbOther Relationship: Janssen Oncology, Novartis Matthew G. KrebsHonoraria: RocheConsulting or Advisory Role: Roche, Achilles Therapeutics, Janssen, Seattle Genetics, OM Pharma, BayerSpeakers' Bureau: Roche, JanssenResearch Funding: RocheTravel, Accommodations, Expenses: AstraZeneca, BerGenBio, Immutep Karen L. ReckampConsulting or Advisory Role: Amgen, Tesaro, Boehringer Ingelheim, Takeda, AstraZeneca, Seattle Genetics, Calithera Biosciences, Genentech, Blueprint Medicines, Daiichi Sankyo/Lilly, EMD Serono, Janssen Oncology, Lilly, Merck KGaAResearch Funding: Bristol Myers Squibb, Pfizer, ARIAD, Xcovery, Adaptimmune, Genentech/Roche, Boehringer Ingelheim, AbbVie, ACEA Biosciences, Loxo, GlaxoSmithKline, Guardant Health, Janssen Oncology, Seattle Genetics, Zeno Pharmaceuticals, Calithera Biosciences, Elevation Oncology, Daiichi Sankyo/Astra Zeneca John XieEmployment: JNJStock and Other Ownership Interests: JNJ Joshua C. CurtinEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & Johnson/Janssen Nahor Haddish-BerhaneEmployment: Johnson & JohnsonStock and Other Ownership Interests: Johnson & Johnson Amy RoshakEmployment: Janssen Pharmaceutical Company of Johnson & JohnsonStock and Other Ownership Interests: Johnson & Johnson Dawn MillingtonEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & Johnson/JanssenTravel, Accommodations, Expenses: Janssen Research & Development Patricia LorenziniEmployment: Janssen Pharmaceuticals of Johnson & Johnson Meena ThayuEmployment: Janssen OncologyStock and Other Ownership Interests: Johnson & Johnson/JanssenOther Relationship: Janssen Oncology Roland E. KnoblauchEmployment: Johnson & JohnsonStock and Other Ownership Interests: Johnson & JohnsonTravel, Accommodations, Expenses: Johnson & Johnson Byoung Chul ChoLeadership: Gencurix Inc, Interpark Bio Convergence CorpStock and Other Ownership Interests: TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics, KANAPH Therapeutic Inc, Cyrus Therapeutics, Interpark Bio Convergence CorpConsulting or Advisory Role: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Yuhan, Pfizer, Janssen, Takeda, MSD, Ono Pharmaceutical, Eli Lilly, Medpacto, Blueprint Medicines, KANAPH Therapeutic Inc, Brigebio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec IncResearch Funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines, Interpark Bio Convergence CorpPatents, Royalties, Other Intellectual Property: Champions OncologyOther Relationship: DAAN BiotherapeuticsNo other potential conflicts of interest were reported.

Background: To ensure safe delivery of oncologic care during the COVID-19 pandemic, telemedicine has been rapidly adopted. However, little data exist on the impact of telemedicine on quality and accessibility of oncologic care. This study assessed whether conducting an office visit for thoracic oncology patients via telemedicine affected time to treatment initiation and accessibility., Methods: This was a retrospective cohort study of patients with thoracic malignancies seen by a multidisciplinary team during the first surge of COVID-19 cases in Philadelphia (March 1 to June 30, 2020). Patients with an index visit for a new phase of care, defined as a new diagnosis, local recurrence, or newly discovered metastatic disease, were included., Results: 240 distinct patients with thoracic malignancies were seen: 132 patients (55.0%) were seen initially in-person vs 108 (45.0%) via telemedicine. The majority of visits were for a diagnosis of a new thoracic cancer (87.5%). Among newly diagnosed patients referred to the thoracic oncology team, the median time from referral to initial visit was significantly shorter amongst the patients seen via telemedicine vs. in-person (median 5.0 vs. 6.5 days, p < 0.001). Patients received surgery (32.5%), radiation (24.2%), or systemic therapy (30.4%). Time from initial visit to treatment initiation by modality did not differ by telemedicine vs in-person: surgery (22 vs 16 days, p = 0.47), radiation (27.5 vs 27.5 days, p = 0.86, systemic therapy (15 vs 13 days, p = 0.45)., Conclusions: Rapid adoption of telemedicine allowed timely delivery of oncologic care during the initial surge of the COVID19 pandemic by a thoracic oncology multi-disciplinary clinic., (© 2021. The Author(s).)

Objectives: To assess the prognostic significance of oligometastatic versus polymetastatic disease in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC), and to evaluate the impact of definitive tumor directed therapy on the survival outcomes for patients with oligometastatic disease when compared to systemic therapy., Materials and Methods: This was a retrospective observational cohort study of patients with HPV-associated OPSCC who developed distant metachronous metastatic disease after undergoing initial primary surgical management from 2008 to 2017. We classified patients based on the extent of metastatic disease [Oligometastatic (≤5 metastases) and polymetastatic (>5 metastases)], and the initial treatment of metastatic disease [definitive tumor directed therapy (all metastases treated with surgery or radiotherapy) versus upfront systemic therapy]., Results: Among 676 patients undergoing primary surgical management for HPV-associated OPSCC, 39 patients (5.8%) developed metastases after a median follow-up of 29.6 months (range 4.5-127.0). Of the 34 metastatic patients who met study criteria, 26 (76.5%) were oligometastatic and 8 (23.5%) were polymetastatic. Oligometastatic patients had improved median overall survival (OS) compared to polymetastatic patients (47.9 vs. 22.7 months, p = 0.036). For oligometastatic patients, definitive tumor directed therapy was associated with an improved median progression free survival (not reached vs 6.13 months, p = 0.001) and median OS (not reached vs 40.7 months, p = 0.004)., Conclusion: In a cohort of patients surgically treated for HPV-associated OPSCC, metachronous metastatic disease was uncommon and, in most cases, considered oligometastatic. Oligometastasis portends a favorable prognosis and definitive tumor directed therapy may be associated with improved overall survival in these patients. Future multi-institutional efforts are warranted to further demonstrate the impact of definitive tumor directed therapy on disease outcomes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Patients with oropharyngeal cancer who undergo transoral robotic surgery (TORS) and have high-risk features generally receive adjuvant chemoradiotherapy or trimodality therapy (TMT). The notion that TMT leads to high toxicity is largely based on studies that included human papilloma virus (HPV)-negative cancers and/or nonrobotic surgery; we sought to describe outcomes in HPV-associated oropharyngeal squamous cell cancer (HPV + OPSCC) undergoing TORS-TMT., Methods: In consecutive patients with HPV + OPSCC receiving TMT at an academic center from 2010 to 2017, survival was estimated using Kaplan-Meier methodology, and toxicities were ascertained via chart review., Results: In our cohort of 178 patients, 5-year survival was 93.6%. Feeding tube rates were 25.8% at therapy completion and 0.7% at 1 year. Rates of grade ≥ 3 kidney injury, anemia, and neutropenia in cisplatin-treated patients were 2.7%, 3.4%, and 11.0%, respectively., Conclusions: Patients with HPV + OPSCC who underwent TORS-TMT had excellent survival and low rates of toxicity and feeding tube dependence. These outcomes compare favorably to historical cohorts treated with definitive chemoradiotherapy., (© 2021 Wiley Periodicals LLC.)

Background: Patients with human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) continue to experience disappointing outcomes following chemoradiotherapy (CRT) and appreciable morbidity following historical surgical approaches. We aimed to investigate the oncologic outcomes and perioperative morbidity of a transoral robotic surgery (TORS) approach to surgically resectable HPV-negative OPSCC., Methods: Retrospective analysis HPV-negative OPSCC patients who underwent TORS, neck dissection and pathology-guided adjuvant therapy (2005-2017)., Results: Fifty-six patients (91.1% stage III/IV) were included. Three-year overall survival, locoregional control, and disease-free survival were 85.5%, 84.4%, and 73.6%, respectively (median follow-up 30.6 months, interquartile range 18.4-66.6). Eighteen (32.1%) patients underwent adjuvant radiotherapy and 20 (39.3%) underwent adjuvant CRT. Perioperative mortality occurred in one (1.8%) patient and hemorrhage occurred in two (3.6%) patients. Long-term gastrostomy and tracheostomy rates were 5.4% and 0.0%, respectively., Conclusion: The TORS approach for resectable HPV-negative OPSCC can achieve encouraging oncologic outcomes with infrequent morbidity., (© 2021 Wiley Periodicals LLC.)

Objectives: To determine whether up-front trans-oral robotic surgery (TORS) for clinically-staged locally-advanced human papillomavirus (HPV)-related oropharyngeal cancer is associated with oncologic and survival outcomes comparable to early-stage (cT1/T2) tumors., Materials and Methods: Retrospective cohort study of 628 patients with HPV-related oropharyngeal cancer who underwent up-front TORS from 2007 to 2017. Patients were stratified into two cohorts based on early-stage (cT1/2) versus locally-advanced (cT3/4) tumor at presentation., Results: We identified 589 patients who presented with early-stage tumors, and 39 patients with locally-advanced tumors. Of these, 73% of patients required adjuvant radiation, and 33% required adjuvant chemoradiation. There was no significant difference in the administration of adjuvant radiation or chemoradiation between the two cohorts. Patients in the locally-advanced disease cohort were significantly more likely to have Stage II/III disease by clinical and pathologic criteria by American Joint Committee on Cancer 8th edition criteria (p < 0.001). However, there was no significant difference in 5-year overall survival (OS) or recurrence-free survival (RFS) based on Kaplan-Meier survival estimates between the two cohorts (p = 0.75, 0.6, respectively), with estimated OS of 91% at 5 years, and estimated RFS of 86% at 5 years across the study population., Conclusions: Up-front TORS offers favorable survival outcomes for appropriately selected locally-advanced cases of HPV-related oropharyngeal cancer. Furthermore, up-front TORS is comparably effective in allowing avoidance of adjuvant therapy, particularly chemotherapy, in both cT1/T2 and locally-advanced HPV-positive oropharyngeal cancer. In the absence of clear technical contraindication to surgery, cT3/T4 classification should not be considered an absolute contraindication to surgery., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Some patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) do not receive guideline-recommended postoperative radiation therapy (PORT) following primary transoral robotic surgery (TORS)., Methods: Three-hundred and sixty-four patients with treatment-naïve, HPV-associated OPSCC were recommended to receive PORT based on clinicopathological features following TORS. Patients were stratified based on if they received PORT. Oncologic outcomes were compared., Results: The 3-year locoregional failure (LRF) was 32% in patients who did not receive PORT and 4% in patients who received PORT (P < .001). Despite increased LRF, avoiding PORT was not associated with increased 3-year distant metastasis rates (8% vs 4%, P = .56) or worse 3-year survival (95% vs 98%, P = .34). Recurrences in the surgery alone cohort varied between local and regional sites and were often successfully salvaged., Conclusions: Patients with HPV-associated OPSCC who do not receive indicated PORT have an increased risk of LRF but similar survival due to high salvage rates., (© 2020 Wiley Periodicals LLC.)

Although the majority of patients with metastatic non-small-cell lung cancer (mNSCLC) lacking a detectable targetable mutation will receive pembrolizumab-based therapy in the frontline setting, predicting which patients will experience a durable clinical benefit (DCB) remains challenging., Materials and Methods: Patients with mNSCLC receiving pembrolizumab monotherapy or in combination with chemotherapy underwent a 74-gene next-generation sequencing panel on blood samples obtained at baseline and at 9 weeks. The change in circulating tumor DNA levels on-therapy (molecular response) was quantified using a ratio calculation with response defined by a > 50% decrease in mean variant allele fraction. Patient response was assessed using RECIST 1.1; DCB was defined as complete or partial response or stable disease that lasted > 6 months. Progression-free survival and overall survival were recorded., Results: Among 67 patients, 51 (76.1%) had > 1 variant detected at a variant allele fraction > 0.3% and thus were eligible for calculation of molecular response from paired baseline and 9-week samples. Molecular response values were significantly lower in patients with an objective radiologic response (log mean 1.25% v 27.7%, P < .001). Patients achieving a DCB had significantly lower molecular response values compared to patients with no durable benefit (log mean 3.5% v 49.4%, P < .001). Molecular responders had significantly longer progression-free survival (hazard ratio, 0.25; 95% CI, 0.13 to 0.50) and overall survival (hazard ratio, 0.27; 95% CI, 0.12 to 0.64) compared with molecular nonresponders., Conclusion: Molecular response assessment using circulating tumor DNA may serve as a noninvasive, on-therapy predictor of response to pembrolizumab-based therapy in addition to standard of care imaging in mNSCLC. This strategy requires validation in independent prospective studies., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Jeffrey C. ThompsonConsulting or Advisory Role: OncoCyte, AstraZeneca, Guardant HealthErica L. CarpenterHonoraria: AstraZeneca Consulting or Advisory Role: Bristol-Myers Squibb Research Funding: Merck, Janssen, Becton Dickinson, United Health Group Patents, Royalties, Other Intellectual Property: Invention disclosure titled "Methods and Compositions for Treating Neuroblastoma", and invention disclosure titled "Methods and Compositions for Identifying, Diagnosing and Treating Neuroblastoma" Travel, Accommodations, Expenses: AstraZeneca, Foundation Medicine,Katie QuinnEmployment: Guardant Health Stock and Other Ownership Interests: Guardant HealthCarin R. EspenschiedEmployment: Guardant Health Stock and Other Ownership Interests: Guardant HealthAllysia MakEmployment: Guardant Health Stock and Other Ownership Interests: Guardant HealthLesli A. KiedrowskiEmployment: Guardant Health Stock and Other Ownership Interests: Guardant HealthMartina LefterovaEmployment: Guardant Health Stock and Other Ownership Interests: Guardant Health Consulting or Advisory Role: PersonalisRebecca J. NagyEmployment: Guardant Health Stock and Other Ownership Interests: Guardant HealthSharyn I. KatzConsulting or Advisory Role: Trizell Research Funding: NovartisChristine A. CiunciHonoraria: Imedex Research Funding: Celgene, Merck, Bristol-Myers Squibb, MacroGenicsJoshua M. BaumlConsulting or Advisory Role: Bristol-Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, Guardant Health, Takeda, Novartis, Janssen, Ayala Pharmaceuticals, Regeneron, Inivata, Foundation Medicine Research Funding: Merck, Carevive Systems, Novartis, Incyte, Bayer, Janssen, AstraZeneca, Takeda, Amgen, Pfizer, Mirati TherapeuticsRoger B. CohenConsulting or Advisory Role: Heat Biologics, Innate Pharma, Cantargia AB, Genocea Biosciences, AstraZeneca Research Funding: Heat Biologics, Merck, Celldex, Innate Pharma, Kyn therapeutics, Xencor, Genocea Biosciences Travel, Accommodations, Expenses: Heat Biologics, Innate Pharma, Genocea BiosciencesCorey J. LangerHonoraria: Bristol-Myers Squibb, Genentech/Roche, Lilly/ImClone, AstraZeneca, Takeda Science Foundation, Merck Consulting or Advisory Role: Genentech/Roche, Lilly/ImClone, Merck, Abbott Biotherapeutics, Bayer/Onyx, Clarient, Clovis Oncology, Celgene, Cancer Support Community, Bristol-Myers Squibb, ARIAD, Takeda, AstraZeneca, Pfizer, Novocure, Gilead Sciences Research Funding: Merck, Advantagene, Clovis Oncology, Celgene, Inovio Pharmaceuticals, Ariad, GlaxoSmithKline, Genentech/Roche, Stem CentRx, Lilly, Trizell Other Relationship: Lilly, Amgen, Peregrine Pharmaceuticals, SyntaCharu AggarwalConsulting or Advisory Role: Genentech, Lilly, Celgene, Merck, AstraZeneca Speakers' Bureau: AstraZeneca, Roche/Genentech, An Immediate Family Member Research Funding: Genentech/Roche, Incyte, Macrogenics, Merck Sharp & Dohme, AstraZeneca/MedImmune No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Background: Patients with metastatic non-small-cell lung cancer (mNSCLC) and untreated brain metastases (BM) have been excluded from most trials of immune checkpoint inhibitors (ICIs). Real-world evidence on efficacy and survival outcomes of ICIs in patients with BM is limited., Patients and Methods: We conducted a single-center retrospective study of patients with mNSCLC treated with pembrolizumab with or without chemotherapy and compared progression-free survival (PFS) and overall survival (OS) between patients with and without BM using Kaplan-Meier and Cox methodology. We also characterized systemic and intracranial objective response rate (ORR) and treatment details, including timing of cranial irradiation., Results: Between Augutst 2013 and December 2018, 570 patients with mNSCLC treated with pembrolizumab-based therapy were analyzed. Of 126 (22.1%) patients with BM, 96 (76.2%) had treated BM (local therapy prior to pembrolizumab), and 30 (23.8%) had untreated BM. Of patients with untreated BM, 17 (56.7%) underwent radiation within 30 days after pembrolizumab initiation. In the remaining 13 (43.3%) treated with pembrolizumab-based therapy alone, intracranial ORR was 36.4%. Patients with and without BM did not have significantly different systemic ORR (27.8% vs. 29.7%; P = .671), PFS (mPFS 9.2 vs. 7.7 months; P = .609), or OS (mOS 18.0 vs. 18.7 months; P = .966). Factors associated with improved survival on Cox analysis included female gender, performance status, adenocarcinoma histology, and first-line therapy., Conclusions: Patients with BM did not have inferior survival to patients without BM after treatment with pembrolizumab-based therapy. In the current era, BM may not automatically confer inferior survival, and should not exclude patients from receiving pembrolizumab-based therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The APOLLO investigators showed that next-generation sequencing of cerebrospinal fluid can reveal molecular alterations-how should this affect our management approach? See related article by Xing et al., p. 6168 ., (©2020 American Association for Cancer Research.)

Background: Neutrophil-to-lymphocyte ratio (NLR) is a biomarker that is correlated with systemic inflammation and poor prognosis in solid tumors. We investigated the value of NLR in predicting survival in a large population of head and neck cancer patients in the United States., Methods: We performed a retrospective cohort study of Veterans Affairs patients with head and neck squamous cell carcinoma (HNSCC) diagnosed between January 2000 and December 2017. We compared 5-year overall survival and cancer-specific survival for different NLR tertiles using cox proportional hazards modeling with adjustment for covariates., Results: The primary cohort consisted of 14 644 subjects of which 99% were male. Relative to patients with NLRs in the lower tertile, patients with NLRs in the top tertile had an 71% increased hazard of all-cause mortality (P < .001) and 44% increased hazard of cancer-specific mortality (P < .001) at 5 years., Conclusions: Elevated NLR in HNSCC confers a poor prognosis., (© 2020 Wiley Periodicals LLC.)

Coronavirus disease 2019 (COVID-19) has had a devastating impact around the world. With high rates of transmission and no curative therapies or vaccine yet available, the current cornerstone of management focuses on prevention by social distancing. This includes decreased health care contact for patients. Patients with lung cancer are a particularly vulnerable population, where the risk of mortality from cancer must now be balanced by the potential risk of a life-threatening infection. In these unprecedented times, a collaborative and multidisciplinary approach is required to streamline but not compromise care. We have developed guidelines at our academic cancer center to standardize management of patients with lung cancer across our health care system and provide guidance to the larger oncology community. We recommend that general principles of lung cancer treatment continue to be followed in most cases where delays could result in rapid cancer progression. We recognize that our recommendations may change over time based on clinical resources and the evolving nature of the COVID-19 pandemic. In principle, however, treatment paradigms must continue to be individualized, with careful consideration of risks and benefits of continuing or altering lung cancer-directed therapy.

Importance: Conservative management (ie, active surveillance or watchful waiting) is a guideline-based strategy for men with low-risk and intermediate-risk prostate cancer. However, use of conservative management is controversial for African American patients, who have worse prostate cancer outcomes compared with White patients., Objective: To examine the association of African American race with the receipt and duration of conservative management in the Veterans Health Administration (VA), a large equal-access health system., Design, Setting, and Participants: This cohort study used data from the VA Corporate Data Warehouse for 51 543 African American and non-Hispanic White veterans diagnosed with low-risk and intermediate-risk localized node-negative prostate cancer between January 1, 2004, and December 31, 2013. Men who did not receive continuous VA care were excluded. Data were analyzed from February 1 to June 30, 2020., Exposures: All patients received either definitive therapy (ie, prostatectomy, radiation, androgen deprivation therapy) or conservative management (ie, active surveillance or watchful waiting)., Main Outcomes and Measures: Receipt of conservative management and (for patients receiving conservative management) time from diagnosis to definitive therapy., Results: The median (interquartile range) age of the 51 543 veterans in our cohort was 65 (61-70) years, and 14 830 veterans (28.8%) were African American individuals. Compared with White veterans, African American veterans were more likely to have intermediate-risk disease (18 988 [51.7%] vs 8526 [57.5%]), 3 or more comorbidities (15 438 [42.1%] vs 7614 [51.3%]), and high disability-related or income-related needs (9078 [24.7%] vs 4614 [31.1%]). Overall, 20 606 veterans (40.0%) received conservative management. African American veterans with low-risk disease (adjusted relative risk, 0.95; 95% CI, 0.92-0.98; P < .001) and intermediate-risk disease (adjusted relative risk, 0.92; 95% CI, 0.87-0.97; P = .002) were less likely to receive conservative management than White veterans. Compared with White veterans, African American veterans with low-risk disease (adjusted hazard ratio, 1.71; 95% CI, 1.50-1.95; P < .001) and intermediate-risk disease (adjusted hazard ratio, 1.46; 95% CI, 1.27-1.69; P < .001) who received conservative management were more likely to receive definitive therapy within 5 years of diagnosis (restricted mean survival time [SE] at 5 years, 1679 [5.3] days vs 1740 [2.4] days; P < .001)., Conclusions and Relevance: In this study, conservative management was less commonly used and less durable for African American veterans than for White veterans. Prospective trials should assess the comparative effectiveness of conservative management in African American men with prostate cancer.

Purpose: The role of plasma-based tumor mutation burden (pTMB) in predicting response to pembrolizumab-based first-line standard-of-care therapy for metastatic non-small cell lung cancer (mNSCLC) has not been explored., Experimental Design: A 500-gene next-generation sequencing panel was used to assess pTMB. Sixty-six patients with newly diagnosed mNSCLC starting first-line pembrolizumab-based therapy, either alone or in combination with chemotherapy, were enrolled (Clinicaltrial.gov identifier: NCT03047616). Response was assessed using RECIST 1.1. Associations were made for patient characteristics, 6-month durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS)., Results: Of 66 patients, 52 (78.8%) were pTMB-evaluable. Median pTMB was 16.8 mutations per megabase (mut/Mb; range, 1.9-52.5) and was significantly higher for patients achieving DCB compared with no durable benefit (21.3 mut/Mb vs. 12.4 mut/Mb, P = 0.003). For patients with pTMB ≥ 16 mut/Mb, median PFS was 14.1 versus 4.7 months for patients with pTMB < 16 mut/Mb [HR, 0.30 (0.16-0.60); P < 0.001]. Median OS for patients with pTMB ≥ 16 was not reached versus 8.8 months for patients with pTMB < 16 mut/Mb [HR, 0.48 (0.22-1.03); P = 0.061]. Mutations in ERBB2 exon 20, STK11, KEAP1 , or PTEN were more common in patients with no DCB. A combination of pTMB ≥ 16 and absence of negative predictor mutations was associated with PFS [HR, 0.24 (0.11-0.49); P < 0.001] and OS [HR, 0.31 (0.13-0.74); P = 0.009]., Conclusions: pTMB ≥ 16 mut/Mb is associated with improved PFS after first-line standard-of-care pembrolizumab-based therapy in mNSCLC. STK11/KEAP1/PTEN and ERBB2 mutations may help identify pTMB-high patients unlikely to respond. These results should be validated in larger prospective studies., (©2020 American Association for Cancer Research.)

Purpose: This trial tested the safety and efficacy of a novel, deintensified radiation therapy (RT) approach after initial surgical resection for patients with human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC)., Methods and Materials: This single-arm phase 2 prospective clinical trial enrolled 60 patients with stage pT1-pT2 N1-3 HPV-associated OPSCC treated with transoral robotic surgery (TORS) and selective neck dissection at a single institution between May 2014 and September 2017. Patients had favorable features at the primary site (negative surgical margins ≥2 mm, no perineural invasion, and no lymphovascular invasion) but required adjuvant therapy based on lymph node involvement. Surgeries were all performed at a high-volume head and neck cancer center with expertise in TORS. Patients received postoperative RT to at-risk areas in the involved neck (60-66 Gy) and uninvolved neck (54 Gy). The resected primary site was treated as an active avoidance structure in the treatment planning of postoperative RT. Concurrent chemotherapy was administered for patients with extranodal extension., Results: Median follow-up of the 60 patients enrolled was 2.4 years (range, 8.5-53.8 months). A single patient recurred at the primary site, for 2-year local control of 98.3%. One patient (1.7%) developed a regional neck recurrence, and 2 patients (3.3%) developed distant metastases. Measured 2-year local recurrence-free survival was 97.9% (95% confidence interval, 86.1%-99.7%). Overall survival was 100% at the time of analysis. The mean radiation dose to the primary site was 36.9 Gy (standard deviation, 10.3 Gy). Two patients (3.3%) experienced late soft tissue necrosis in the primary site surgical bed that resolved within 2 months. Feeding tube dependence rates were 0% during RT, 3.3% temporarily during follow-up, and 0% at last follow-up., Conclusions: Deintensified postoperative RT that avoids the resected primary tumor site and targets only the at-risk neck after TORS for selected patients with HPV-associated OPSCC may be safe and is worthy of further study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: There are no established imaging biomarkers that predict response during chemoradiation for patients with locally advanced non-small cell lung carcinoma. At our institution, proton therapy (PT) patients undergo repeat computed tomography (CT) simulations twice during radiation. We hypothesized that tumor regression measured on these scans would separate early and late responders and that early response would translate into better outcomes., Methods and Materials: Patients underwent CT simulations before starting PT (CT0) and between weeks 1 to 3 (CT1) and weeks 4 to 7 (CT2) of PT. Primary tumor volume (TVR) and nodal volume (NVR) reduction were calculated at CT1 and CT2. Based on recursive partitioning analysis, early response at CT1 and CT2 was defined as ≥20% and ≥40%, respectively. Locoregional and overall progression-free survival (PFS), distant metastasis-free survival, and overall survival by response status were measured using Kaplan-Meier analysis., Results: Ninety-seven patients with locally advanced non-small cell lung carcinoma underwent definitive PT to a median dose of 66.6 Gy with concurrent chemotherapy. Median TVR and NVR at CT1 were 19% (0-79%) and 19% (0-75%), respectively. At CT2, they were 33% (2-98%) and 35% (0-89%), respectively. With a median follow-up of 25 months, the median overall survival and PFS for the entire cohort was 24.9 and 13.2 months, respectively. Compared with patients with TVR and NVR <20% at T1 and <40% at T2, patients with TVR and NVR ≥20% at CT1 and ≥40% at CT2 had improved median locoregional PFS (27.15 vs 12.97 months for TVR ≥40% vs <40%, P < .01, and 25.67 vs 12.09 months for NVR ≥40% vs <40%, P < .01) and median PFS (22.7 vs 9.2 months, P < .01, and 20.3 vs 7.9 months, P < .01), confirmed on multivariate Cox regression analysis., Conclusions: Significantly improved outcomes in patients with early responses to therapy, as measured by TVR and NVR, were seen. Further study is warranted to determine whether treatment intensification will improve outcomes in slow-responding patients., (Copyright © 2019. Published by Elsevier Inc.)

: Background: Recurrent respiratory papillomatosis (RRP) is a rare disorder characterized by the generation of papillomas of the aerodigestive tract, usually associated with human papilloma virus (HPV) subtypes 6, 11. INO-3106 is a DNA plasmid-based immunotherapy targeting E6 and E7 proteins of HPV6, in order to create a robust immune T cell response., Methods: Testing of INO-3016 in animal models confirmed immunogenicity of the DNA-based therapy. A single-site open-label Phase 1 study was initiated for patients with HPV6-positive RRP. Patients were dosed with INO-3106 with or without INO-9012, a DNA plasmid immunotherapy that encodes IL-12, delivered intramuscularly (IM) in combination with electroporation (EP) with the CELLECTRA ® device. Patients received an escalating dose of INO-3106, 3 mg once and then 6 mg for three additional doses, each dose three weeks apart, with the third and fourth doses co-administered with INO-9012. The primary objective of the study was to evaluate the safety and tolerability of INO-3106 with and without INO-9012. The secondary objective was to determine cellular immune responses to INO-3106 with and without INO-9012. Exploratory objectives included preliminary clinical efficacy to the therapy., Results: Three patients were enrolled in this study, of which two had RRP. Study therapy was well-tolerated, with no related serious adverse events and all related adverse events (AEs) were low-grade. Injection site pain was the most common related AE reported. Immunogenicity was evidenced by multiple immune assays showing engagement and expansion of an HPV6-specific cellular response, including cytotoxic T cells. Preliminary efficacy was demonstrated in patients with RRP in the form of reduction in need for surgical intervention for papilloma growth. Prior to intervention, both patients required surgical intervention approximately every 180 days. One patient demonstrated a greater than three-fold increase in surgery avoidance (584 days) and the other patient remains completely surgery-free as of the last contact at 915 days, a greater than 5-fold increase in surgery interval., Conclusion: INO-3106 with and without INO-9012 was well tolerated, immunogenic and demonstrated preliminary efficacy in patients with HPV6-associated RRP aerodigestive lesions. Further clinical study is indicated., Competing Interests: Authors employed by Inovio Pharmaceuticals are supported financially by that entity. Non-Inovio authors have no conflicts to disclose.

Objective: One approach to reduce treatment-related morbidity for human papilloma virus (HPV)-associated tonsil cancer is omitting radiotherapy to the contralateral neck. Pathologic risk factors for early contralateral neck disease, however, are poorly understood. We report on the risk contralateral neck failures from the time of pre-operative diagnostic imaging to time of planning for adjuvant radiation in a single institution series of HPV-associated tonsillar cancer patients undergoing surgery followed by radiotherapy (RT)., Methods: Retrospective analysis of 123 patients with T1 - T3 HPV-positive tonsillar squamous cell carcinoma treated between 2010 and 2016 with transoral robotic surgery and selective ipsilateral neck dissection followed by adjuvant RT. Contralateral neck recurrence was classified as the detection of a pathologic node in the contralateral neck prior to initiation of adjuvant RT., Results: Seven patients (5.7%) developed contralateral neck disease/failure between the time of pre-operative diagnostic neck imaging and time of planning of adjuvant radiation. Increased ratio of positive/resected nodes [odds ratio (OR) 1.073, p = 0.005] was significantly associated with increased risk of contralateral neck recurrence, with a trend found for close/positive margins (OR 5.355, p = 0.06), tumor size (OR 2.046, p = 0.09), and total number of nodes positive (OR 1.179, p = 0.062)., Conclusions: Patients who develop very early contralateral neck disease, between completion of ipsilateral neck dissection and the initiation of radiotherapy, have a higher ratio of positive nodes to total nodes resected in the ipsilateral neck. These findings suggest that proper selection of patients for omission of treatment of the contralateral, node-negative neck should be made with this in mind, with future studies needed to document the impact on toxicity and disease outcomes from such an approach., Advances in Knowledge: Pathologic risk factors in the dissected, ipsilateral neck in patients with tonsil cancer may inform the risk of contralateral neck failure. Patient selection for future, prospective efforts to examine sparing of the contralateral neck need to be based with these risk factors in mind.

Background: For patients with head and neck squamous cell carcinoma (SCC) undergoing surgery followed by postoperative radiotherapy (PORT), time from surgery to completion of adjuvant therapy, "package time" impacts locoregional control (LRC). However, the significance of package time in HPV+ oropharyngeal SCC (OPSCC) is unknown., Methods: We examined patients undergoing TORS resection with PORT for HPV+ OPSCC from January 2010 to December 2015 with ≥18 months follow-up (n = 267). A cutoff of 15 weeks was used to delineate patients into short and long package time groups. LRC loss was defined as any recurrence after surgery., Results: Prolonged package time >15 weeks was associated with inferior LRC in this HPV+ OPSCC cohort, driven primarily by interval from surgery to PORT initiation. Multivariate analysis showed that package time and T classification are both independently associated with LRC., Conclusions: Among HPV+ OPSCC, prolongation of package time appears to compromise LRC, but not survival., (© 2019 Wiley Periodicals, Inc.)

Importance: Patients with oligometastatic non-small cell lung cancer (NSCLC) may benefit from locally ablative therapy (LAT) such as surgery or stereotactic radiotherapy. Prior studies were conducted before the advent of immunotherapy, and a strong biological rationale for the use of immunotherapy exists in a minimal residual disease state., Objective: To evaluate whether the addition of pembrolizumab after LAT improves outcomes for patients with oligometastatic NSCLC., Design, Setting, and Participants: This single-arm phase 2 trial of pembrolizumab therapy was performed from February 1, 2015, through September 30, 2017, at an academic referral cancer center. The 51 eligible patients enrolled had oligometastatic NSCLC (≤4 metastatic sites) and had completed LAT to all known sites of disease. Data were analyzed from February 1, 2015, to August 23, 2018., Interventions: Within 4 to 12 weeks of completing LAT, patients began intravenous pembrolizumab therapy, 200 mg every 21 days, for 8 cycles, with provision to continue to 16 cycles in the absence of progressive disease or untoward toxic effects., Main Outcomes and Measures: The 2 primary efficacy end points were progression-free survival (PFS) from the start of LAT (PFS-L), which preceded enrollment in the trial, and PFS from the start of pembrolizumab therapy (PFS-P). The study was powered for comparison with historical data on the first efficacy end point. Secondary outcomes included overall survival, safety, and quality of life as measured by the Functional Assessment of Cancer Therapy-Lung instrument., Results: Of 51 patients enrolled, 45 (24 men [53%]; median age, 64 years [range, 46-82 years]) received pembrolizumab. At the time of analysis, 24 patients had progressive disease or had died. Median PFS-L was 19.1 months (95% CI, 9.4-28.7 months), significantly greater than the historical median of 6.6 months (P = .005). Median PFS-P was 18.7 months (95% CI, 10.1-27.1 months). Eleven patients died. Overall mean (SE) survival rate at 12 months was 90.9% (4.3%); at 24 months, 77.5% (6.7%). Neither programmed death ligand 1 expression nor CD8 T-cell tumor infiltration was associated with PFS-L. Pembrolizumab after LAT yielded no new safety signals and no reduction in quality of life., Conclusions and Relevance: Pembrolizumab after LAT for oligometastatic NSCLC appears to improve PFS with no reduction in quality of life., Trial Registration: ClinicalTrials.gov identifier: NCT02316002.

Background: Concurrent chemoradiotherapy is an established component of the nonoperative management of locally advanced head and neck squamous cell carcinoma (HNSCC), but the standard dose of 100 mg/m2 cisplatin every 3 weeks is associated with clinically significant toxicity. Interest in a more tolerable regimen has led to the widespread use of weekly lower dose cisplatin, but few randomized trials have compared these approaches., Methods: We examined outcomes of patients with stage III-IVb HNSCC treated with definitive intent chemoradiotherapy using either high-dose cisplatin (HDC) or low-dose cisplatin (LDC), using population-based Veterans Affairs data. In an intent-to-treat analysis, patients were assigned to the HDC vs LDC group according to the dose of their first cycle. Variables potentially influencing treatment decisions including cancer site, stage, smoking/alcohol use, and comorbidities were used to generate propensity scores (PS) for the use of HDC. We compared overall survival (OS) by treatment group using Cox regression, adjusting for PS. We then determined the risk of toxicities using PS-adjusted logistic regression., Results: A total of 2901 patients were included in the analysis; 2200 received HDC (mean initial dose 100 mg/m2). The mean initial dose of LDC was 40 mg/m2. After PS adjustment, HDC was not associated with improved OS over LDC (hazard ratio = 0.94, 95% confidence interval = 0.80 to 1.04). Adjusting for PS, HDC was associated with an increased risk of acute kidney injury, neutropenia, dehydration/electrolyte disturbance, and hearing loss., Conclusion: In this large, population-based study of US military veterans, LDC was associated with similar survival to HDC in the nonoperative definitive management of locally advanced HNSCC of the oral cavity, oropharynx, and hypopharynx/larynx. HDC was associated with statistically significantly more toxicity than LDC. Adoption of LDC may reduce toxicity burden while maintaining OS., (Published by Oxford University Press 2018.)

Background: The addition of cisplatin or cetuximab to radiation therapy (RT) improves outcomes in comparison with RT alone in the nonoperative management of head and neck squamous cell carcinoma (HNSCC), but limited data exist for comparing these approaches. Using Veterans Health Affairs data, this study compared the outcomes of patients treated with RT plus cisplatin or cetuximab., Methods: Patients with stage III to IVb HNSCC who had been treated nonsurgically with RT and cisplatin or cetuximab from 2000 to 2016 within the Veterans Health Affairs system were identified. Patients were analyzed by the drug used in the first treatment cycle (intent to treat). Overall survival (OS) was compared by treatment group with Cox regression models, and propensity score (PS) methods were used to account for a treatment allocation bias. The risk of toxicities was determined, with logistic regression models fit into propensity-matched cohorts., Results: A total of 4520 patients were included in the analysis with a median follow-up of 3 years: 83% received cisplatin. Cisplatin patients were younger (P < .001) and had fewer comorbidities (P < .001). In an unmatched analysis, cetuximab was associated with inferior OS (P < .001). After PS matching, cetuximab treatment remained statistically significantly associated with inferior OS (1.7 vs 4.1 years; hazard ratio, 1.61; 95% confidence interval, 1.44-1.79; P < .001). These differences remained significant across all primary HNSCC subsites and in comparison with low- and high-dose cisplatin., Conclusions: Cetuximab with RT yields inferior OS in comparison with cisplatin for the nonoperative management of stage III to IVb HNSCC. According to this study, cisplatin may be the most appropriate partner for RT in this setting., (© 2018 American Cancer Society.)

Importance: The clinical implications of adding plasma-based circulating tumor DNA next-generation sequencing (NGS) to tissue NGS for targetable mutation detection in non-small cell lung cancer (NSCLC) have not been formally assessed., Objective: To determine whether plasma NGS testing was associated with improved mutation detection and enhanced delivery of personalized therapy in a real-world clinical setting., Design, Setting, and Participants: This prospective cohort study enrolled 323 patients with metastatic NSCLC who had plasma testing ordered as part of routine clinical management. Plasma NGS was performed using a 73-gene commercial platform. Patients were enrolled at the Hospital of the University of Pennsylvania from April 1, 2016, through January 2, 2018. The database was locked for follow-up and analyses on January 2, 2018, with a median follow-up of 7 months (range, 1-21 months)., Main Outcomes and Measures: The number of patients with targetable alterations detected with plasma and tissue NGS; the association between the allele fractions (AFs) of mutations detected in tissue and plasma; and the association of response rate with the plasma AF of the targeted mutations., Results: Among the 323 patients with NSCLC (60.1% female; median age, 65 years [range, 33-93 years]), therapeutically targetable mutations were detected in EGFR, ALK, MET, BRCA1, ROS1, RET, ERBB2, or BRAF for 113 (35.0%) overall. Ninety-four patients (29.1%) had plasma testing only at the discretion of the treating physician or patient preference. Among the 94 patients with plasma testing alone, 31 (33.0%) had a therapeutically targetable mutation detected, thus obviating the need for an invasive biopsy. Among the remaining 229 patients who had concurrent plasma and tissue NGS or were unable to have tissue NGS, a therapeutically targetable mutation was detected in tissue alone for 47 patients (20.5%), whereas the addition of plasma testing increased this number to 82 (35.8%). Thirty-six of 42 patients (85.7%) who received a targeted therapy based on the plasma result achieved a complete or a partial response or stable disease. The plasma-based targeted mutation AF had no correlation with depth of Response Evaluation Criteria in Solid Tumors response (r = -0.121; P = .45)., Conclusions and Relevance: Integration of plasma NGS testing into the routine management of stage IV NSCLC demonstrates a marked increase of the detection of therapeutically targetable mutations and improved delivery of molecularly guided therapy.

Purpose: The STK11 gene encodes a serine/threonine protein kinase that regulates cell polarity and functions as a tumor suppressor. Patients with non-small-cell lung cancer (NSCLC) and STK11 mutations often have other co-mutations. We evaluated the impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy for patients with metastatic or recurrent NSCLC that harbors STK11 mutations., Methods: We conducted a retrospective review of patients with metastatic NSCLC and STK11 mutations treated at the University of Pennsylvania. STK11 mutations were identified through next-generation sequencing (NGS) in tissue or plasma. Cox proportional hazard models were used to determine the relationship between STK11 co-mutations and survival outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS)., Results: From February 2013 to December 2016, samples from 1,385 patients with NSCLC were analyzed by NGS; of these, 77 patients (6%) harbored an STK11 mutation (n = 56, tissue; n = 21, plasma). Of the 62 patients included, 18 had an STK11 mutation alone, 19 had STK11/KRAS, 18 had STK11/TP53, and seven had STK11/KRAS/TP53. Patients with STK11/KRAS co-mutations had a worse median PFS (2.4 months) compared with STK11 alone (5.1 months; log-rank P = .048), STK11/TP53 (4.3 months; log-rank P = .043), and STK11/KRAS/ TP53 (13 months; log-rank P = .03). Patients with STK11/KRAS co-mutation experienced shorter median OS (7.1 months) compared with STK11 alone (16.1 months; log-rank P < .001), STK11/TP53 (28.3 months; log-rank P < .001), and STK11/KRAS/TP53 (22 months; log-rank P = .025)., Conclusion: Among patients with advanced NSCLC and STK11 mutations treated with first-line systemic therapy, co-mutation with KRAS was associated with significantly worse PFS and OS. By contrast, co-mutation of STK11 with TP53 conferred a better prognosis., Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.