Search

Background: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1., Objective: The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles., Patients and Methods: Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1-3 and 8-10 of a 21-day treatment cycle., Results: Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥ 3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 1.2 months (SCLC biomarker amplified)., Conclusion: Adavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors., Trial Registration: ClinicalTrials.gov identifier NCT02482311; registered June 2015., (© 2023. The Author(s).)

Background: First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival., Patients and Methods: Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed., Results: In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population., Conclusion: Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC., Competing Interests: Disclosure HB reports advisory/consulting fees, travel, accommodation, and expenses from Amgen, Bristol Myers Squibb, Genentech, Lilly, Merck, and Novartis; advisory/consulting fees from AbbVie, AstraZeneca, BioNTech AG, Boehringer Ingelheim, Cantargia AB, EMD Serono, Genmab, HUYA Bioscience International, Nuclaei, Pfizer, PharmaMar, Regeneron, Rgenix, Sonnet, Takeda, and Trovagene; honoraria from Amgen, Axiom Biotechnologies, Bristol Myers Squibb, Celgene, and Pfizer; research funding from Bristol Myers Squibb, Celgene, Lilly, Merck, and Millennium; stock interest with Nuclaei, Rgenix, and Sonnet; travel, accommodation, and expenses from Clovis Oncology; data safety monitoring board with Incyte and University of Pennsylvania; and ad boards with Guardant, Natera, and OncoCyte. TEC reports advisory/consulting fees, travel, accommodation, and expenses from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen, Merck Sharp & Dohme (MSD), Novartis/GlaxoSmithKline, Pfizer, Roche, Sanofi, and Servier. J-SL reports advisory/consulting fees from AstraZeneca and Ono Pharmaceutical. AP reports speaker fees, expert testimony, travel, accommodation, and expenses from Boehringer Ingelheim, Bristol Myers Squibb, and MSD; speaker fees and expert testimony from Roche, speaker fees from Pfizer; and speaker fees, travel, accommodation, and expenses from AstraZeneca. RBC reports advisory/consulting fees from AstraZeneca, Bristol Myers Squibb, MSD, Roche, and Takeda. MG reports advisory fees from Celularity and Guardant 360; and speaker fees from Guardant 360. YO reports advisory/consulting fees, honoraria, and research funding from AstraZeneca and Ono Pharmaceutical; and honoraria and research funding from Bristol Myers Squibb Japan. MN reports advisory/consulting fees, honoraria, and research funding from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Lilly, MSD, Ono Pharmaceuticals, Taiho Pharmaceutical, and Takeda; advisory/consulting fees from AbbVie and Teijin Pharma; honoraria and research funding from Janssen, Merck, Novartis, and Pfizer; and honoraria from Boehringer Ingelheim and Nippon Kayaku. JG reports grant support from Advaxis, AstraZeneca, Bristol Myers Squibb, Genentech, Merck, and Pfizer; consulting and writing fees from Bristol Myers Squibb; and consulting fees from AstraZeneca, Genentech, and Pfizer. NR reports consulting fees and honoraria from AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Genentech, Merck, and Roche; research funding from Merck; honoraria from Novartis and Celgene; expert testimony fees from Bristol Myers Squibb and Celgene; speaker’s bureau fees from Bristol Myers Squibb; personal fees from AbbVie, Amgen, Jazz, Regeneron, and Sanofi; other fees from AbbVie; and a grant from Amgen. DRS reports grant support from Aeglea BioTherapeutics, Agios, Apollomics, Arcus, Arrys Therapeutics, Astellas Pharma, Bayer, BeiGene, BIND Therapeutics, BioNTech, Blueprint Medicine, Calithera, Celgene, Celldex, Clovis Oncology, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Eli Lilly, EMD Serono, Evelo, G1 Therapeutics, GlaxoSmithKline, GRAIL, Hutchinson MediPharma, ImClone Systems, ImmunoGen, Incyte, Ipsen, Janssen, Kronos Bio, Loxo Oncology, MacroGenics, MedImmune, Merck, Molecular Partners, Molecular Templates, Nektar, Neon Therapeutics, Novocure, Oncologie, PTC Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tesaro, Tizona Therapeutics, Transgene, University of Texas-Southwestern, and Verastem; and consulting support from Amgen, BeiGene, Curio Science, Eli Lilly, EMD Serono, Evidera, Exelixis, GlaxoSmithKline, Intellisphere, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Molecular Templates, Novocure, Puma Biotechnology, Regeneron, and Sanofi-Aventis. SSR reports advisory/consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sanyo, Eisai, Genentech/Roche, GlaxoSmithKline, Lilly, Merck, Sanofi, Takeda; and research funding from Advaxis, AstraZeneca, Bristol Myers Squibb, EMD Serono, Genmab, GlaxoSmithKline, Merck, Takeda, Tesaro. LGPA reports travel, accommodation, and expenses from AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Roche, and Takeda; honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, Merck Serono, Mirati, MSD, Novartis, Pfizer, PharmaMar, Roche/Genetech, Sanofi, Servier, and Takeda; speaker fees from Bristol Myers Squibb, Lilly, Merck Serono, MSD Oncology, Pfizer, and Roche/Genentech; research funding from AstraZeneca, Bristol Myers Squibb, MSD, PharmaMar; and personal fees from Altum Sequencing and Genomica. JFG reports consulting fees and honoraria from AstraZeneca, Blueprint, Bristol Myers Squibb, EMD Serono, Gilead, Glyde Bio, iTeos, Karyopharm, Loxo/Lilly, Merck, Moderna, Novartis, Oncorus, Pfizer, Regeneron, Silverback Therapeutics, and Takeda; grant support from Adaptimmune, Alexo, Array Biopharma, Blueprint, Bristol Myers Squibb, Jounce, Merck, Moderna, Novartis, and Tesaro; and an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. MR reports advisory/consulting fees, travel, accommodation, and expenses from AbbVie and Amgen; advisory/consulting fees, speaker fees, expert testimony, travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck, MSD, Novartis, Pfizer, and Roche; and advisory/consulting fees from Samsung. MM reports advisory/consulting fees Alfasigma, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Incyte, iOnctura, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, and SciClone. KJO reports advisory/consulting fees, speaker fees, expert testimony, honoraria, travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Lilly Oncology, MSD, Pfizer, and Roche; advisory/consulting fees, speaker fees, expert testimony and honoraria from Novartis; advisory/consulting fees, speaker fees, and honoraria from Teva; advisory/consulting fees and honoraria from Natera, Takeda, Tristar, and Yuhan; and being a shareholder at Carpe Vitae Pharmaceuticals, DGC diagnostics, Foundation Medicine, and RepLuca Pharmaceuticals. AM reports employment and stock interest with Bristol Myers Squibb. FN reports employment at Bristol Myers Squibb; and ownership/stock interest with AstraZeneca, Johnson & Johnson, and Eli Lilly. PT reports employment and stock interest with Bristol Myers Squibb. MDH reports advisory/consulting fees from Achilles, Adagene, Adicet, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Da Volaterra, Eli Lilly, Genentech, Genzyme/Sanofi, Immunai, Instill Bio, Janssen, Mana Therapeutics, Merk, Mirati, Pact Pharma, Regeneron, Roche, and Shattuck Labs; research funding from Bristol Myers Squibb; stock interest with Arcus, Factorial, Immunai, and Shattuck Labs; a patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics (PGDx); after the completion of this work, MDH began as an employee (and equity holder) at AstraZeneca. JRB reports advisory/consultancy fees and research funding from Bristol Myers Squibb; advisory/consultancy fees from Amgen, AstraZeneca, Genentech, GlaxoSmithKline, Merck, Regeneron, and Sanofi; consultancy fees and honoraria from Janssen; and advisory/consultancy fees and other from Roche/Genentech. SA has declared no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Background: For patients with advanced non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitor (ICPI) and chemotherapy (chemo) ICPI represent two distinct first-line standard-of-care regimens without clear and established biomarkers to inform the optimal choice for individual patients. Here, we examined the complementary roles of tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) to inform first-line therapy using a large real-world (rw) data set., Materials and Methods: The study included patients with NSCLC from an rw de-identified clinico-genomic database. All patients underwent genomic testing using Foundation Medicine's tissue comprehensive genomic profiling assay and PD-L1 IHC assay scored for tumor cell staining (TS)., Results: Of 2165 patients included in the analysis, 150 exhibited durable benefit from first-line ICPI regimens (these patients were enriched for PD-L1 TS ≥50, non-squamous histology, and TMB ≥20 mutations/megabase (muts/Mb)). Comparing low TMB (<10 muts/Mb), high TMB (10-19 muts/Mb), and very high TMB (≥20 muts/Mb) receiving ICPI alone, we observed a stepwise increase in median rwPFS (real world-progression free survival) (6.5, 7.5, 17.2 months) and rwOS (real world-overall survival) (10.1, 11.8, 26.9 months) as TMB increased. In the low PD-L1 (TS <50%) cohort, TMB <20 muts/Mb showed a more favorable rwPFS (HR: 0.56 (95% CI: 0.40 to 0.79)) and rwOS (HR 0.74 (95% CI: 0.58 to 0.96)) on chemoICPI when compared with ICPI alone while the point estimate in rwPFS favored monoICPI in the TMB ≥20 muts/Mb cohort, the CI is wide and does not reach statistical significance (HR: 1.68 (95% CI: 0.52 to 5.48))., Conclusion: This study provides evidence that higher TMB cut-offs, such as 20 muts/Mb, can identify patients with prolonged benefit from ICPI. TMB ≥20 muts/Mb is a potential biomarker that may identify patients in whom an ICPI without chemo could be considered, even in the setting of lower PD-L1 levels. Prospective validation of these findings could increase access to chemo-sparing regimens for the first-line treatment of advanced NSCLC., Competing Interests: Competing interests: RSPH, GL, AS, RG, LZ, KM, JSR, KT, and GRO are employees of Foundation Medicine, a wholly owned subsidiary of Roche and these employees have equity interest in Roche. DC is an employee/paid consultant for AbbVie, Adaptimmune, Agenus, Amgen, Ariad, AstraZeneca, Biocept, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, EMD Serono, Foundation Medicine, Genentech/Roche, Gritstone, Guardant Health, Inovio, Merck, MSD, Novartis, Palobiofarma, Pfizer, prIME Oncology, and Takeda, and reports receiving commercial research grants from Bristol Myers Squibb. JSR has consulting/advisory board AstraZeneca, Curadev, Daiichi-Sankyo, Jazz Pharmaceuticals, Medtronic, Pharma Mar. DS reports receiving research funding from AstraZeneca, Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, AbbVie, Foundation Medicine, GlaxoSmithKline, Eli Lilly, Merck, Nektar, Takeda, Amgen, University of Texas Southwestern Medical Center–Simmons Cancer Center, G1 Therapeutics, Neon Therapeutics, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Astellas Pharma, GRAIL, Transgene, Aeglea Therapeutics, Tesaro, Ipsen, Janssen, BIND Therapeutics, Eisai, and ImClone Systems; and consulting, advisory, and/or speakers’ bureau fees from AstraZeneca, Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, AbbVie, Foundation Medicine, GlaxoSmithKline, Eli Lilly, Merck, Moderna, Nektar, Takeda, Amgen, TRM Oncology, Precision Oncology, Evelo Therapeutics, Illumina, Pharmamar, EMD Serono, Aptitude Health, Dracen Pharmaceuticals, Iksuda Therapeutics, Molecular Templates, Seattle Genetics, TRIPTYCH Health Partners, and Intellisphere., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This study examined patients with advanced non-small-cell lung cancer who received long-term avelumab (anti-PD-L1) in a large phase Ib trial (JAVELIN Solid Tumor). Methods: Patients receiving >2 years of avelumab were reviewed and exploratory descriptive analyses were conducted. Results: Individuals with varying baseline characteristics who had received up to 6 years of avelumab were reviewed. Overall, 37/340 (10.9%) had received ≥2 years of treatment; in this subgroup, best response was complete response in 5.4%, partial response in 59.5% and stable disease in 29.7%; 51.4% had continued treatment beyond disease progression. Conclusions: In this study, 11% of patients with advanced non-small-cell lung cancer received ≥2 years of avelumab treatment and experienced prolonged response or continued clinical benefit. Clinical Trial Registration: NCT02395172 (ClinicalTrials.gov).

Introduction: In the JAVELIN Lung 200 trial, avelumab (anti-programmed death-ligand 1 [PD-L1] antibody) did not significantly prolong overall survival (OS) versus docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report greater than 2-year follow-up data., Methods: Patients with stage IIIB or IV or recurrent NSCLC with disease progression after platinum-doublet chemotherapy were randomized 1:1 to avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m 2 every 3 weeks. The primary end point was OS in patients with PD-L1+ tumors (greater than or equal to 1% tumor cell expression; IHC 73-10 pharmDx assay)., Results: Of 792 patients, 529 had PD-L1+ tumors (264 versus 265 in the avelumab versus docetaxel arms, respectively). As of March 4, 2019, median duration of follow-up for OS in the PD-L1+ population was 35.4 months in the avelumab arm and 34.7 months in the docetaxel arm; study treatment was ongoing in 25 (9.5%) versus 0 patients, respectively. In the PD-L1+ population, 2-year OS rates (95% confidence interval [CI]) with avelumab versus docetaxel were 29.9% (24.5%-35.5%) versus 20.5% (15.6%-25.8%); in greater than or equal to 50% PD-L1+ subgroups, 2-year OS rates were 36.4% (29.1%-43.7%) versus 17.7% (11.8%-24.7%) and in the greater than or equal to 80% subgroup were 40.2% (31.3%-49.0%) versus 20.3% (12.9%-28.8%), respectively. Median duration of response (investigator assessed) was 19.1 months (95% CI: 10.8-34.8) versus 5.7 months (95% CI: 4.1-8.3). Safety profiles for both arms were consistent with the primary analysis., Conclusions: Although the JAVELIN Lung 200 primary analysis (reported previously) revealed that avelumab did not significantly prolong OS versus docetaxel in patients with platinum-treated PD-L1+ NSCLC, posthoc analyses at 2 years of follow-up revealed that 2-year OS rates were doubled with avelumab in subgroups with higher PD-L1 expression (greater than or equal to 50% and greater than or equal to 80%)., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC., Patients and Methods: CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS)., Results: Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%., Conclusion: Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab., Competing Interests: Disclosure DRS: consulting or advisory role: Aptitude Health (Inst), AstraZeneca (Inst), Bayer (Inst), Bristol Myers Squibb (Inst), Celgene (Inst), Dracen Pharmaceuticals (Inst), EMD Serono (Inst), Evelo Biosciences (Inst), Genentech/Roche (Inst), GlaxoSmithKline (Inst), Iksuda Therapeutics (Inst), Illumina (Inst), Merck (Inst), Molecular Templates (Inst), Nektar Therapeutics (Inst), Novartis (Inst), Pfizer (Inst), PharmaMar (Inst), Roche (Inst), Seattle Genetics (Inst), Takeda (Inst), TRIPTYCH Health Partners (Inst), TRM Oncology, Williams and Connolly LLP (Inst); research funding: Aeglea BioTherapeutics (Inst), Astellas (Inst), AstraZeneca (Inst), BIND Therapeutics (Inst), Bristol Myers Squibb (Inst), Celgene (Inst), Celldex (Inst), Clovis (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Eli Lilly (Inst), EMD Serono (Inst), G1 Therapeutics (Inst), Genentech (Inst), GRAIL (Inst), ImClone Systems (Inst), ImmunoGen (Inst), Ipsen (Inst), Janssen (Inst), MedImmune (Inst), Merck (Inst), Molecular Partners (Inst), Nektar (Inst), Neon (Inst), Novartis (Inst), Takeda (Inst), Transgene (Inst), University of Texas Southwestern (Inst); travel, accommodations, expenses: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Janssen, Merck, Novartis, Seattle Genetics, Spectrum Pharmaceuticals, and Takeda. DV: honoraria: AstraZeneca; consulting or advisory role: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche; travel, accommodations, expenses: AstraZeneca. TEC: consulting or advisory role: A&D Pharma, Amgen, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Genentech/Roche, Janssen, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Servier; travel, accommodations, expenses: A&D Pharma, Amgen, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Ipsen, Janssen, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, Servier. SG: consulting or advisory role: Bristol Myers Squibb, Nektar; research funding: Bristol Myers Squibb (Inst), Genentech/Roche (Inst), Iovance Biotherapeutics (Inst). SP: consultation/advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Foundation Medicine, Illumina, Janssen, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, PharmaMar, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, and Vaccibody; talk in a company's organized public event: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Illumina, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Sanofi, Takeda; research finding: Amgen (Inst), AstraZeneca (Inst), Biodesix (inst), Boehringer Ingelheim (inst), Bristol Myers Squibb (Inst), Clovis (Inst), Illumina (Inst), Merck Sharp & Dohme (Inst), Merck Serono (Inst), Novartis (Inst), Pfizer (Inst), and Roche/Genentech (Inst). LH: consulting or advisory role: AbbVie, AstraZeneca, Bristol Myers Squibb, EMB Serono, Genentech/Roche, Incyte, Merck, Xcovery; research funding: Boehringer Ingelheim, Bristol Myers Squibb, Xcovery. CA-V: consulting or advisory role: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Takeda; travel, accommodations, expenses: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Takeda. NPA: Consulting or advisory role: Merck Sharp & Dohme, Pfizer, Roche; travel, accommodations, expenses: Eli Lilly, Pfizer, Roche. OJ-V: honoraria: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Merck Sharp & Dohme; consulting or advisory role: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Genentech/Roche, Merck Sharp & Dohme, Pfizer, Takeda; travel, accommodations, expenses: Merck Sharp & Dohme, Roche. MS: speaker's bureau: Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital. JW: honoraria: AbbVie, Amgen, AstraZeneca, Blueprint, Bristol Myers Squibb, Boehringer Ingelheim, Chugai, Eli Lilly, Ignyta, Janssen, Loxo, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda; research funding: Bristol Myers Squibb, Johnson and Johnson, Novartis, Pfizer. SA: consulting or advisory role: Achilles Therapeutics, Amgen, AstraZeneca, Bristol Myers Squibb, Cellular Biomedicine Group, Celsius, GlaxoSmithKline, Memgen, Merck, RAPT Therapeutics, Samyang Biopharm, Venn Therapeutics; travel, accommodations, expenses: Achilles Therapeutics, Amgen, Bristol Myers Squibb, Celsius, GlaxoSmithKline, Merck, RAPT Therapeutics. KN: honoraria: Astellas Pharma, AstraZeneca K.K., Bristol Myers Squibb, Carenet Health, Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Hisamitsu Pharmaceutical Co., Inc., KYORIN Pharmaceutical Co., Ltd., Medical Review Co., Ltd., MEDICUS SHUPPAN Publishers Co., Ltd., Merck Sharp & Dohme K.K., Nanzando Co., Ltd., Nichi-Iko Pharmaceutical Co., Ltd., Nikkei Business Publications, Inc., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., ONO Pharmaceutical Co., Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd, Thermo Fisher Scientific K.K., YODOSHA Co., Ltd., Yomiuri Telecasting Corporation; consulting or advisory role: Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd; research funding: AbbVie, Astellas Pharma, AstraZeneca K.K., Bayer Yakuhin, Ltd., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., CMIC Shift Zero K.K., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., EPS Corporation, IQVIA., ICON Japan K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Serono Co., Ltd., Merck Sharp & Dohme K.K., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., ONO Pharmaceutical Co., Ltd., Parexel International Corp., Pfizer Japan Inc., Quintiles Inc., SymBio Pharmaceuticals Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. JF: former employee of Bristol Myers Squibb. CB employment: Bristol Myers Squibb. DP employment: Bristol Myers Squibb. PD employment: Bristol Myers Squibb, former employee of Johnson and Johnson. HC employment: Bristol Myers Squibb. MR: consulting or advisory role: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda; speaker's bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda; research funding: Boehringer Ingelheim, Bristol Myers Squibb; travel, accommodations, expenses: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda. All other authors have declared no conflicts of interest. Data sharing Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/clinical-trials-and-research/disclosure-commitment.html., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: We retrospectively investigated the impact of tumor PD-L1 expression and prior chemoradiotherapy (CRT)-related variables on patient-reported outcomes (PROs) from PACIFIC. Patients & methods: PACIFIC was a Phase III study of durvalumab versus placebo after CRT in patients with unresectable, stage III non-small-cell lung cancer. If available, pre-CRT tumor tissue was tested for PD-L1 tumor-cell expression, scored at prespecified (25%) and post-hoc (1%) cut-offs. PROs were assessed using EORTC QLQ C30/-LC13. Results: Similar to the intent-to-treat (ITT) population, most PROs remained stable over time across PD-L1 and CRT subgroups, with few clinically relevant differences between treatment arms. Time to deterioration was generally similar to the ITT population. Conclusion: Neither PD-L1 expression nor prior CRT-related variables influenced PROs with durvalumab therapy. Clinical trial registration: NCT02125461 (ClinicalTrials.gov).

Objectives: The JAVELIN Lung 200 phase 3 trial did not meet its primary endpoint of improving overall survival (OS) with avelumab vs docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report post hoc analyses assessing the effects of subsequent immune checkpoint inhibitor (ICI) treatment on OS., Material and Methods: Patients with stage IIIB/IV NSCLC progressed following platinum-doublet therapy were randomized to receive avelumab or docetaxel. OS was analyzed in the PD-L1+ population (≥1% of tumor cells) and full analysis set (PD-L1+ or PD-L1-). Effects of subsequent ICI (after permanent discontinuation of study treatment) on OS were analyzed using a preplanned naive sensitivity analysis and post hoc inverse probability of censoring weighting (IPCW) analysis. Subgroups with or without subsequent ICI treatment were analyzed using descriptive statistics., Results: In the avelumab and docetaxel arms, a subsequent ICI was received by 16/396 (4.0 %) and 104/396 (26.3 %) after a median of 10.5 months (range, 3.9-20.4) and 5.7 months (range, 0.1-24.4), respectively. Some subgroups showed trends for higher subsequent ICI treatment, including patients with non-squamous NSCLC (avelumab arm, 4.3 % vs docetaxel arm, 32.1 %) or with a baseline ECOG performance status of 0 (6.3 % vs 31.3 %); those enrolled in the early recruitment wave (11.6 % vs 54.3 %), or enrolled in the US/Western Europe (2.8 % vs 45.5 %) or Asia (11.0 % vs 35.4 %); and non-white patients (10.1 % vs 35.0 %). The hazard ratio for OS with avelumab vs docetaxel was lower in the IPCW analysis than in the naive sensitivity analysis (PD-L1+ population: 0.80 [95 % CI, 0.62-1.04] vs 0.86 [95 % CI, 0.68-1.09], respectively)., Conclusion: In the JAVELIN Lung 200 trial, avelumab showed clinical activity as second-line treatment for patients with advanced NSCLC. Post hoc analyses suggest that the primary OS analysis may have been confounded by subsequent ICI use in the docetaxel arm. ClinicalTrials.gov identifier: NCT02395172., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study., Patients and Methods: Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors received an initial flat dose of quavonlimab as monotherapy [25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3)] followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab [25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E)] plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints., Results: Thirty-nine patients were enrolled in DE [n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3)] and 134 in DC [n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E)]. Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% [95% confidence interval (CI), 24.9-56.7; arm A], 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR., Conclusions: Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D., Competing Interests: Disclosure RP reports a consultant role for Karyopharm Therapeutics and BioLineRx. JB reports an advisory board role for Roche, AstraZeneca, Pfizer, Takeda, Boehringer Ingelheim, and Bayer; and a consultant role for MSD, BMS, Novartis, and AbbVie. DWR reports research grants from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. M-JA reports an advisory board role for AstraZeneca, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, ONO, BMS, Takeda, Amgen, Novartis, and Roche; and a consultant role for Alpha Pharmaceutical Company, AstraZeneca, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, ONO, BMS, Takeda, Amgen, Novartis, and Roche. KY reports honorarium received from promotional activities from Chugai Pharma, AstraZeneca, Lilly Japan, Novartis, Kirin, Bristol Myers Squibb Japan, and Taiho. D-WK reports travel and accommodation support for advisory board meeting attendance from Amgen and Daiichi Sankyo. AN reports an advisory board role for MSD, BMS, Roche, and AstraZeneca. MS reports honoraria received from promotional activities from AstraZeneca, MSD, Chugai, Taiho, Pfizer, Nippon Kayaku, Boehringer Ingelheim, Bristol Myers Squibb, ONO, Novartis, and Eli Lilly; and research grants from Chugai, AstraZeneca, MSD, Pfizer, Boehringer Ingelheim, Bristol Myers Squibb, ONO, Novartis, Eli Lilly, AbbVie, Ignyta, and Takeda. DHL reports honoraria for lecturing or consulting from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ChongKunDang, CJ Healthcare, Eli Lilly, Janssen, Menarini, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Mundipharma, Novartis, Roche, ST Cube, and Takeda; and travel accommodations from Takeda and Blueprint Medicines. DRS reports leadership for Centennial Medical Center; consulting or advisory role for Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, AstraZeneca, Pfizer, Boehringer Ingelheim, AbbVie, Foundation Medicine, GlaxoSmithKline, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Moderna Therapeutics, Nektar, Takeda, Amgen, TRM Oncology, Precision Oncology, Evelo Therapeutics, Illumina, and PharmaMar; research funding (institution) from Genentech/Roche, Novartis, Celgene, Bristol Myers Squibb, Lilly, AstraZeneca, Pfizer, Boehringer Ingelheim, University of Texas Southwestern Medical Center – Simmons Cancer Center, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, AbbVie, GlaxoSmithKline, G1 Therapeutics, Neon Therapeutics, Takeda, Foundation Medicine, Nektar, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Acerta Pharma, OncoGenex, Astellas Pharm, GRAIL, Transgene, Ipsen, ARMO BioSciences, Amgen, and Millennium; and travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Celgene, Lilly, EMD Serono, Bristol Myers Squibb, Genentech, Genzyme, Intuitive Surgical, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Pfizer, Purdue Pharma, Spectrum Pharmaceuticals, and Sysmex. SS is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. XL is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. JC is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and has stock ownership interests in Merck & Co., Inc., Kenilworth, NJ, USA. AC is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and has stock ownership interests in Merck & Co., Inc., Kenilworth, NJ, USA. AC is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. RAA is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. BCC reports a speakers bureau role for Novartis; an advisory board role for Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, ONO, Dizal Pharma, and MSD; a consultant role for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, ONO, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and MSD; stock ownership interests in TheraCanVac Inc., Gencurix Inc., and BridgeBio Therapeutics; honoraria from promotional activities for Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, ONO, Dizal Pharma, and MSD; research grants from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; and royalties, intellectual property or patents with Champions Oncology. All other authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Checkpoint inhibitors (CPIs) have been approved to treat metastatic NSCLC. Pegilodecakin + CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS 1 and CYPRESS 2., Methods: CYPRESS 1 (N = 101) and CYPRESS 2 (N = 52) included Eastern Cooperative Oncology Group performance status of 0 to 1 and first-line/second-line metastatic NSCLC, respectively, without known EGFR/ALK mutations. Patients were randomized 1:1; control arms received pembrolizumab (CYPRESS 1) or nivolumab (CYPRESS 2); experimental arms received pegilodecakin + CPI. Patients had programmed death-ligand 1 tumor proportion score of greater than or equal to 50% (CYPRESS 1) or 0% to 49% (CYPRESS 2). Primary end point was objective response rate (ORR) per investigator. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Exploratory end points included immune activation biomarkers., Results: Median follow-up for CYPRESS 1 and CYPRESS 2 was 10.0 and 11.6 months, respectively. Results for pegilodecakin + pembrolizumab versus pembrolizumab were as follows: ORR per investigator 47% versus 44% (OR = 1.1, 95% confidence interval [CI]: 0.5-2.5); median PFS 6.3 versus 6.1 months (hazard ratio [HR] = 0.937, 95% CI: 0.54-1.625); and median OS 16.3 months versus not reached (HR = 1.507, 95% CI: 0.708-3.209). Results per blinded independent central review were consistent. Treatment discontinuation rate owing to adverse events (AEs) doubled in the experimental arm (32% versus 15%). AEs with grade greater than or equal to 3 treatment-related AEs (62% versus 19%) included anemia (20% versus 0%) and thrombocytopenia (12% versus 2%). Results for pegilodecakin + nivolumab versus nivolumab were as follows: ORR per investigator 15% versus 12% (OR = 1.2, 95% CI: 0.3-5.9); median PFS 1.9 versus 1.9 months (HR = 1.006, 95% CI: 0.519-1.951); and median OS 6.7 versus 10.7 months (HR = 1.871, 95% CI: 0.772-4.532). AEs with grade greater than or equal to 3 treatment-related AEs (70.4% versus 16.7%) included anemia (40.7% versus 0%), fatigue (18% versus 0%), and thrombocytopenia (14.8% versus 0%). Biomarker data suggested activation of immunostimulatory signals of interleukin-10R pathway in pegilodecakin-containing arms., Conclusions: Despite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in first-line/second-line NSCLC. Pegilodecakin + CPI has been found to have overall higher toxicity compared with CPI alone, leading to doubling of treatment discontinuation rate owing to AEs., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Avelumab, an antiprogrammed death ligand-1 antibody, is approved as a monotherapy for treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. We report the efficacy and safety of first-line avelumab in advanced non-small cell lung cancer (NSCLC)., Methods: In a phase I expansion cohort of the JAVELIN Solid Tumor trial, patients with treatment-naive, metastatic, or recurrent NSCLC received 10 mg/kg avelumab intravenously every 2 weeks. Endpoints included best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety., Results: Overall, 156 patients were enrolled and treated. Median duration of follow-up was 18.6 months (range, 15 to 23 months). The objective response rate was 19.9% (95% CI, 13.9 to 27.0), including complete response in 3 (1.9%) and partial response in 28 (17.9%). Median DOR was 12.0 months (95% CI, 6.9 to not estimable). Median PFS was 4.0 months (95% CI, 2.7 to 5.4) and the 6-month PFS rate was 38.5% (95% CI, 30.7 to 46.3). Median OS was 14.1 months (95% CI, 11.3 to 16.9) and the 12-month OS rate was 56.6% (95% CI, 48.2 to 64.1). Treatment-related adverse events (TRAEs) occurred in 107 patients (68.6%), including grade ≥3 TRAEs in 19 (12.2%). Immune-related adverse events and infusion-related reactions occurred in 31 (19.9%) and 40 patients (25.6%), respectively. No treatment-related deaths occurred., Conclusion: Avelumab showed antitumor activity with a tolerable safety profile as a first-line treatment in patients with advanced NSCLC. These data support further investigation of avelumab in the phase III JAVELIN Lung 100 study., Trial Registration Details: ClinicalTrials.gov NCT01772004; registered January 21, 2013., Competing Interests: Competing interests: CFV, EFM, NI, and FLC have nothing to disclose. GJ has received research funding from Merck KGaA, Novartis, Pfizer, and Roche; personal fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, and Roche; and non-financial support from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, MedImmune, Merck KGaA, Novartis, Pfizer, and Roche. CHR owns stock in Pfizer. JB has provided advisory and speaker services for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck & Co, Roche, and Servier. KK has received research grants from EMD Serono (a business of Merck KGaA, Darmstadt, Germany) and Merck & Co; has served on advisory boards for EMD Serono and Merck & Co; and has received a honorarium from Merck & Co. JM has received research funding from Merck KGaA; research funding from Amgen, AstraZeneca, Bristol Myers Squibb, EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Incyte, MacroGenics, Merck KGaA, Polynoma LLC, and Sanofi. JCM has provided speaker services for Boehringer Ingelheim and Merck KGaA, and has received travel expenses from Amgen, Eisai, Merck KGaA, and VentiRx Pharmaceuticals. MT has provided advisory and speaker services for Bristol Myers Squibb and Eisai; and advisory services for Array BioPharma, ArQule, Bayer, Blueprint Medicines, Loxo Oncology, Novartis, and Sanofi Genzyme. DS has provided consultancy or advisory services and received research funding from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Foundation Medicine, GlaxoSmithKline, Merck KGaA, Nektar, Novartis, Pfizer, Roche/Genentech, and Takeda Oncology; received travel expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Intuitive Surgical, Merck KGaA, Perdue Pharma, Pfizer, Roche/Genentech, Sanofi Genzyme, Spectrum Pharmaceuticals, and Sysmex; provided consultancy or advisory services for Aptitude Health, Evelo Biosciences, Illumina, Moderna, Pharma Mar, and Precision Oncology; and received research funding from Acerta Pharma, Aeglea Biotherapeutics, ARMO BioSciences, Astellas Pharma, Celldex Therapeutics, Clovis Oncology, Daiichi Sankyo, EMD Serono (a business of Merck KGaA, Darmstadt, Germany), G1 Therapeutics, GRAIL, Ipsen, Neon Therapeutics, Oncogenex Pharmaceuticals, Takeda Oncology, Tesaro, and Transgene, and the University of Texas Southwestern Medical Center—Simmons Cancer Center. DW has provided advisory services for and received travel expenses from Merck KGaA. HJG is an employee of Merck KGaA, Darmstadt, Germany. DZ is an employee of Merck Serono Pharmaceutical R&D Co, Beijing, China; a business of Merck KGaA, Darmstadt, Germany. NM and MB are employees of EMD Serono, Inc; a business of Merck KGaA, Darmstadt, Germany. JLG has received research funding from EMD Serono, Inc (a business of Merck KGaA, Darmstadt, Germany)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression., Patients and Methods: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians)., Results: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups., Conclusions: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions., Competing Interests: Disclosure LP-A is a board member of Genomica and has received honoraria from Roche/Genentech, Eli Lilly, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp and Dohme, AstraZeneca, Merck Serono, Pharmamar, Novartis, Celgene, Sysmex, Amgen, and Incyte, and travel, accommodations or expenses from Roche, AstraZeneca, AstraZeneca Spain, Merck Sharp and Dohme, Bristol-Myers Squibb, Eli Lilly, and Pfizer; AS has received advisory fees from Array BioPharma and Incyte, honoraria from CytomX Therapeutics, AstraZeneca/MedImmune and Merck, research funding from LAM Therapeutics, and institutional research support from Roche, AstraZeneca/MedImmune, Boehringer Ingelheim, Astellas Pharma, Novartis, NewLink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, TrovaGene, Takeda, MacroGenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, and Arch Therapeutics; DR has received honoraria from Merck and Nanobiotix, consultant fees from AstraZeneca and Suvica, and advisory board fees from AstraZeneca, Merck, Genentech, and Nanobiotix; DP has received advisory or lecture fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, and Roche, honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, and Roche, institutional research funding from AstraZeneca, Bristol-Myers Squibb, AbbVie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, and Daiichi Sankyo, and travel, accommodations or expenses from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Roche, Merck, Novartis, prIME Oncology, and Pfizer; DD has received institutional research funding from E.R. Squibb and Sons, AstraZeneca, Boehringer Ingelheim, Genentech, Eli Lilly and Company, Novartis Pharmaceuticals, Pfizer, Celgene, and Roche; AV has received honoraria from AstraZeneca, Gilead, and Seattle Genetics; RH has received advisory fees and honoraria from AstraZeneca, Merck Sharp and Dohme, Novartis, Roche, Bristol-Myers Squibb, and Eli Lilly; SS has received research grants from Varian Medical Systems and ViewRay Inc., and honoraria from AstraZeneca, Eli Lilly, Merck Sharp and Dohme, and Celgene; CJL has received honoraria from Roche/Genentech, Eli Lilly, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp and Dohme, AstraZeneca, Novartis, Celgene, Takeda, and Gilead; and travel, accommodations or expenses from Roche, AstraZeneca, Merck Sharp and Dohme, Bristol-Myers Squibb, Eli Lilly and Pfizer; BAP has received advisory fees from AstraZeneca and Bristol-Myers Squibb; and institutional research support from Bristol-Myers Squibb. A-MB and PAD are full-time employees of AstraZeneca with stock ownership; HB is an independent contractor, funded by AstraZeneca; CW was a full-time employee of AstraZeneca when the work was completed; SJA has received advisory fees from Bristol-Myers Squibb, Novartis, Merck, Boehringer Ingelheim, AstraZeneca/MedImmune, Cellular Biomedicine Group, and Memgen; CF-F has received research funding and travel support from Merck, AstraZeneca, and Elekta, and travel support from Pfizer; the remaining authors declare no potential conflicts of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Background: The VeriStrat test provides accurate predictions of outcomes in all lines of therapy for patients with non-small cell lung cancer (NSCLC). We investigated the predictive and prognostic role of VeriStrat in patients enrolled on the MARQUEE phase III trial of tivantinib plus erlotinib (T+E) versus placebo plus erlotinib (P+E) in previously treated patients with advanced NSCLC., Methods: Pretreatment plasma samples were available for 996 patients and were analyzed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry to generate VeriStrat labels (good, VS-G, or poor, VS-P)., Results: Overall, no significant benefit in overall survival (OS) and progression-free survival (PFS) were observed for the addition of tivantinib to erlotinib. Regardless of treatment arm, patients who were classified as VS-G had significantly longer PFS (3.8 mo for T+E arm, 2.0 mo for P+E arm) and OS (11.6 mo for T+E, 10.2 mo for P+E arm) than patients classified as VS-P (PFS: 1.9 mo for both arms, hazard ratio [HR], 0.584; 95% confidence interval [CI], 0.468-0.733; p < .0001 for T+E, HR, 0.686; 95% CI, 0.546-0.870; p = .0015 for P+E; OS: 4.0 mo for both arms, HR, 0.333; 95% CI, 0.264-0.422; p < .0001 for T+E; HR, 0.449; 95% CI, 0.353-0.576; p < .0001 for P+E). The VS-G population had higher OS than the VS-P population within Eastern Cooperative Oncology Group (ECOG) performance score (PS) categories. VS-G patients on the T+E arm had longer PFS, but not OS, than VS-G patients on the P+E arm ( p = .0108). Among EGFR mutation-positive patients, those with VS-G status had a median OS more than twice that of any other group (OS: 31.6 mo for T+E and 22.8 mo for P+E), whereas VS-P patients had similar survival rates as VS-G, EGFR-wild type patients (OS: 13.7 mo for T+E and 6.5 mo for P+E)., Conclusion: In these analyses, VeriStrat showed a prognostic role within EGOC PS categories and regardless of treatment arm and EGFR status, suggesting that VeriStrat could be used to identify EGFR mutation-positive patients who will have a poor response to EGFR tyrosine kinase inhibitors., Implications for Practice: This study suggests that VeriStrat testing could enhance the prognostic role of performance status and smoking status and replicates findings from other trials that showed that the VeriStrat test identifies EGFR mutation-positive patients likely to have a poor response to EGFR tyrosine kinase inhibitors (TKIs). Although these findings should be confirmed in other populations, VeriStrat use could be considered in EGFR mutation-positive patients as an additional prognostic tool, and these results suggest that EGFR mutation-positive patients with VeriStrat "poor" classification could benefit from other therapeutic agents given in conjunction with TKI monotherapy., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Background: Antibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy., Methods: JAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m 2 every 3 weeks. Randomisation was stratified by PD-L1 expression (≥1% vs <1% of tumour cells), which was measured with the 73-10 assay, and histology (squamous vs non-squamous). The primary endpoint was overall survival, analysed when roughly 337 events (deaths) had occurred in the PD-L1-positive population. Efficacy was analysed in all PD-L1-positive patients (ie, PD-L1 expression in ≥1% of tumour cells) randomly assigned to study treatment (the primary analysis population) and then in all randomly assigned patients through a hierarchical testing procedure. Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02395172. Enrolment is complete, but the trial is ongoing., Findings: Between March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11·4 months [95% CI 9·4-13·9] vs 10·3 months [8·5-13·0]; hazard ratio 0·90 [96% CI 0·72-1·12]; one-sided p=0·16). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3-5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes., Interpretation: Compared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile., Funding: Merck and Pfizer., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs., Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized., Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents., Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.

Background: Bavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of β2 glycoprotein 1 (β2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Key eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS)., Results: A total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel + bavituximab arm and was 10.9 months in the docetaxel + placebo arm (HR 1.06; 95% CI 0.88-1.29; P = 0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82-1.22; P = 0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum β2GP1 levels ≥200 µg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63-1.06; P = 0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26-0.81; P = 0.006)., Conclusions: The combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high β2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation., Clinical Trial Number: NCT01999673.

Purpose In two phase III studies, nivolumab, a programmed death-1 (PD-1) inhibitor antibody, improved overall survival (OS) versus docetaxel in pretreated advanced non-small-cell lung cancer (NSCLC). We report 5-year follow-up results from an early phase I study of nivolumab in this patient population and describe characteristics of 5-year survivors. Patients and Methods Patients with pretreated, advanced NSCLC received nivolumab 1, 3, or 10 mg/kg every 2 weeks in 8-week cycles for up to 96 weeks. OS from the time of first dose was estimated by the Kaplan-Meier method. Results The estimated 5-year OS rate was 16% for all treated patients (N = 129); 5-year OS rates were similar for squamous (16%) and nonsquamous (15%) NSCLC. Of 16 5-year survivors, most (88%) were known current or former smokers. Of 10 5-year survivors with quantifiable PD-1 ligand 1 expression, 70% had ≥ 1% PD-1 ligand 1 expression at baseline. Twelve 5-year survivors (75%) achieved a partial response to nivolumab per Response Evaluation Criteria in Solid Tumors, version 1.0, and two each (12%) had stable disease and progressive disease as best response. Nine 5-year survivors (56%) completed the maximum 96 weeks of nivolumab; four (25%) discontinued owing to adverse events and three (19%) owing to disease progression. As of a November 2016 database lock, 12 5-year survivors (75%) received no subsequent therapy and were without evidence of progressive disease at last follow-up. Conclusions Nivolumab treatment resulted in long-term OS and durable responses in a proportion of patients with pretreated advanced NSCLC. Long-term survivors had diverse baseline and on-treatment characteristics.

Purpose: Nivolumab has been administered using a 60-min infusion time. Reducing this time to 30 min would benefit both patients and infusion facilities. This analysis compared the safety of 30- and 60-min infusions of nivolumab in patients with previously treated advanced non-small cell lung cancer., Methods: CheckMate 153 is an open-label, phase 3b/4, predominantly community-based study ongoing in the United States and Canada. Patients with stage IIIB/IV disease with progression/recurrence after at least one prior systemic therapy received nivolumab 3 mg/kg every 2 weeks over 30 or 60 min for 1 year or until disease progression. The primary outcome overall was to estimate the incidence of grade 3-5 treatment-related select adverse events; a retrospective objective was to estimate the incidence of hypersensitivity/infusion-related reactions (IRRs) with the 30-min infusion. Exploratory pharmacokinetic analyses were performed using a population pharmacokinetics model., Results: Of 1420 patients enrolled, 369 received only 30-min infusions and 368 received only 60-min infusions. Similar frequencies of hypersensitivity/IRRs were noted in patients receiving 30-min [2% (n = 8)] and 60-min [2% (n = 7)] infusions. Grade 3-4 treatment-related hypersensitivity/IRRs led to treatment discontinuation in < 1% of patients in each group; < 1% of patients in each group received systemic corticosteroids. Hypersensitivity/IRRs were managed by dosing interruptions, with minimal impact on total dose received. Nivolumab pharmacokinetics were predicted to be similar in the two groups., Conclusions: Nivolumab infused over 30 min had a comparable safety profile to the 60-min infusion, including a low incidence of IRRs.

Background: Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years' follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC., Patients and Methods: Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses., Results: After 40.3 months' minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50-0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61-0.81). Rates of treatment-related hepatic adverse events (primarily grade 1-2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%)., Conclusions: After 3 years' minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated., Clinical Trial Registration: CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.

Background: Eribulin is a microtubule dynamics inhibitor with a novel mechanism of action. This phase 3 study aimed to compare overall survival (OS) in patients with heavily pretreated non-small cell lung cancer (NSCLC) receiving eribulin to treatment of physician's choice (TPC)., Patients and Methods: Patients with advanced NSCLC who had received ≥2 prior therapies, including platinum-based doublet and epidermal growth factor receptor tyrosine kinase inhibitor, were randomly assigned to receive eribulin or TPC (gemcitabine, pemetrexed, vinorelbine, docetaxel). The primary endpoint was OS. Secondary endpoints were progression-free survival and objective response rate., Results: Five hundred and forty patients were randomized to either eribulin (n = 270) or TPC (n = 270). Median OS for eribulin and TPC was the same: 9.5 months [hazard ratio (HR): 1.16; 95% confidence interval: 0.95-1.41; P = 0.13]. Progression-free survival for eribulin and TPC was 3.0 and 2.8 months, respectively (HR: 1.09; 95% confidence interval: 0.90-1.32; P = 0.39). The objective response rate was 12% for eribulin and 15% for TPC. Clinical benefit rate (eribulin, 57%; TPC, 55%) and disease control rate (eribulin, 63%; TPC, 58%) were similar between treatment arms. The most common adverse event was neutropenia, which occurred in 57% of eribulin patients and 49% of TPC patients at all grades. Other non-hematologic side-effects were manageable and similar in both groups except for peripheral sensory neuropathy (all grades; eribulin, 16%; TPC, 9%)., Conclusion: This phase 3 study did not demonstrate superiority of eribulin over TPC with regard to overall survival. However, eribulin does show activity in the third-line setting for NSCLC., Trial Registration Id: www.ClinicalTrials.gov; NCT01454934., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.

Purpose: Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy., Patients and Methods: Patients with advanced ALK-rearranged NSCLC, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/d. Whole-body and intracranial responses were investigator assessed (according to RECIST version 1.1). Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys (the core-30 and the 13-item lung cancer-specific quality-of-life questionnaires)., Results: All 140 patients enrolled had received two or more previous treatment regimens, and all patients had received crizotinib. The median duration of exposure and the follow-up time with ceritinib were 8.8 months (range, 0.1 to 19.4 months) and 11.3 months (range, 0.1 to 18.9 months), respectively. Investigator-assessed overall response rate was 38.6% (95% CI, 30.5% to 47.2%). Secondary end points, all investigator assessed, included disease control rate (77.1%; 95% CI, 69.3% to 83.8%), time to response (median, 1.8 months; range, 1.6 to 5.6 months), duration of response (median, 9.7 months; 95% CI, 7.1 to 11.1 months), and progression-free survival (median, 5.7 months; 95% CI, 5.4 to 7.6 months). Of 100 patients with baseline brain metastases, 20 had active target lesions at baseline; investigator-assessed intracranial overall response rate was 45.0% (95% CI, 23.1% to 68.5%). The most common adverse events (majority, grade 1 or 2) for all treated patients were nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%). Patient-reported outcomes showed a trend toward improved symptom burden. The global quality-of-life score was maintained during treatment., Conclusion: Consistent with its activity in ASCEND-1, ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients, including those with brain metastases., (© 2016 by American Society of Clinical Oncology.)

Purpose: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors., Experimental Design: Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing., Results: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P < 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 - 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 - 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to ≤10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response., Conclusions: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386-95. ©2016 AACR., (©2016 American Association for Cancer Research.)

Purpose: Bevacizumab used in combination with first-line chemotherapy confers an overall survival (OS) benefit for patients with non-squamous non-small-cell lung cancer (NSCLC). This analysis from the ARIES observational cohort study (OCS) was initiated to evaluate the effect of bevacizumab use beyond disease progression (BBP) on clinical outcomes in patients with NSCLC receiving first-line treatment with bevacizumab and chemotherapy., Methods: The ARIES OCS prospectively enrolled patients from 2006 to 2009 in the United States who had advanced non-squamous NSCLC, received bevacizumab with chemotherapy in the first-line setting, and survived progressive disease (PD). A dichotomous landmark analysis examined post-PD OS (ppOS) in patients who received BBP versus no BBP within 30 days post PD. A time-dependent Cox model assessed the effect of cumulative BBP exposure on ppOS., Results: The ARIES OCS enrolled 1967 patients with first-line NSCLC; 1358 patients had first PD and were alive at the 30-day landmark (351 patients with BBP and 1007 patients with no BBP). The landmark analysis showed that BBP was associated with a lower risk of death (BBP versus No-BBP); hazard ratio [HR], 0.75; 95% confidence interval 0.65-0.86. In the cumulative exposure analysis of 1461 patients who had PD, HRs for ppOS decreased by approximately 4% for each additional 21-day interval of bevacizumab received. Protocol-specified bevacizumab-select adverse events occurred in 14% of BBP patients., Conclusions: BBP was associated with a lower risk of death in patients with NSCLC treated with first-line bevacizumab and chemotherapy. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Purpose: Tivantinib, a MET receptor tyrosine kinase inhibitor, demonstrated increased anticancer activity in preclinical and early clinical studies when combined with erlotinib. Our study aimed to confirm efficacy and safety of the combination in previously treated patients with non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with advanced nonsquamous NSCLC previously treated with one to two systemic regimens, including a platinum doublet, were randomly assigned at a 1:1 ratio to receive erlotinib 150 mg daily plus oral tivantinib 360 mg twice daily (E + T) or erlotinib plus placebo (E + P) until disease progression. Tumor specimens were evaluated for EGFR and KRAS mutations, MET expression, and MET gene amplification. The primary end point was overall survival (OS). Secondary and exploratory objectives included progression-free survival (PFS), OS in molecular subgroups, and safety., Results: The study enrolled 1,048 patients and was discontinued for futility at the interim analysis. OS did not improve with E + T versus E + P (median OS, 8.5 v 7.8 months, respectively; hazard ratio [HR], 0.98; 95% CI, 0.84 to 1.15; P = .81), even though PFS increased (median PFS, 3.6 v 1.9 months; HR, 0.74; 95% CI, 0.62 to 0.89; P < .001). Exploratory subgroup analyses suggested OS improvement in patients with high MET expression (HR, 0.70; 95% CI, 0.49 to 1.01). Most common adverse events occurring with E + T versus E + P were rash (33.1% v 37.3%, respectively), diarrhea (34.6% v 41.0%), asthenia or fatigue (43.5% v 38.1%), and neutropenia (grade 3 to 4; 8.5% v 0.8%)., Conclusion: E + T was well tolerated and increased PFS but did not improve OS in the overall nonsquamous NSCLC population., (© 2015 by American Society of Clinical Oncology.)

Aims: Retrospective analyses from first-line clinical studies in advanced non-small cell lung cancer (NSCLC) have reported conflicting results on progression-free survival (PFS) and overall survival benefits with the addition of bevacizumab to chemotherapy in elderly patients. Here we report effectiveness and safety outcomes by age subgroup for patients with NSCLC in the ARIES observational cohort study., Materials and Methods: ARIES enrolled patients with advanced non-squamous NSCLC who received first-line bevacizumab-containing treatment per physician's choice. Kaplan-Meier estimates were used to calculate medians and 95% confidence intervals for PFS and overall survival for patients aged <65, ≥65, <75 and ≥75 years., Results: In total, 1967 patients receiving first-line treatment with bevacizumab and chemotherapy were enrolled. The median PFS and overall survival values were 6.4 (95% confidence interval = 6.0-6.8) and 14.2 (95% confidence interval = 12.7-15.2) months for patients aged <65 years, respectively, and 6.8 (95% confidence interval = 6.3-7.0) and 12.1 (95% confidence interval = 11.4-13.1) months for patients ≥65 years, respectively. For patients <75 years, the median PFS and overall survival values were 6.6 (95% confidence interval = 6.3-6.9) and 13.5 (95% confidence interval = 12.6-14.5) months, respectively, and 6.6 (95% confidence interval = 5.9-7.1) and 11.6 (95% confidence interval = 10.0-12.5) months, respectively, for patients ≥75 years. Incidence proportions of bevacizumab-associated adverse events were generally similar across all age groups., Conclusions: Data from the ARIES study suggest that treatment with bevacizumab in combination with chemotherapy is a viable first-line treatment option for elderly bevacizumab-eligible patients with advanced non-squamous NSCLC., (Copyright © 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC., Patients and Methods: The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0-1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization., Results: Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145)., Conclusions: Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: This preplanned subset analysis of the phase III MONET1 study aimed to determine whether motesanib combined with carboplatin/paclitaxel (C/P) would result in improved overall survival (OS) versus chemotherapy alone, in a subset of Asian patients with nonsquamous nonsmall-cell lung cancer (NSCLC)., Patients and Methods: Patients with nonsquamous NSCLC (stage IIIB/IV or recurrent) and no prior systemic therapy for advanced disease were randomized to IV carboplatin (AUC, 6 mg/ml min) and paclitaxel (200 mg/m2) for up to six 3-week cycles, plus either oral motesanib 125 mg q.d. or placebo. Primary end point was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety., Results: Two hundred twenty-seven Asian patients from MONET1 were included in this descriptive analysis. Median OS was 20.9 months in the motesanib plus C/P arm and 14.5 months in the placebo plus C/P arm (P=0.0223); median PFS was 7.0 and 5.3 months, respectively, (P=0.0004); and ORR was 62% and 27%, respectively, (P<0.0001). Grade≥3 adverse events were more common in the motesanib plus C/P arm versus placebo plus C/P (79% versus 61%)., Conclusion: In this preplanned subset analysis of Asian patients with nonsquamous NSCLC, motesanib plus C/P significantly improved OS, PFS, and ORR versus placebo plus C/P., Clinical Trial Number: NCT00460317.

Treatments for non-small cell lung cancer (NSCLC) are based on the broad categories of squamous or non-squamous histology. Frontline treatment options include pemetrexed and cisplatin, pemetrexed and a taxane, gemcitabine with cisplatin, and the addition of bevacizumab to a taxane and carboplatin. Pemetrexed is used for maintenance therapy for non-squamous NSCLC, whereas patients with squamous NSCLC lack easy options for maintenance therapy. nab-Paclitaxel overcomes the solubility and toxicity issues of solvent-based paclitaxel, and the albumin in nab-paclitaxel improves the concentration of the drug in the tumor. A recent phase III trial in NSCLC compared nab-paclitaxel with carboplatin versus solvent-based paclitaxel with carboplatin, and found improved overall response rates (ORRs) in the nab-paclitaxel arm (33% vs 25%; P=.005). In a subset analysis, NSCLC patients with squamous histology had a higher ORR (41%) with nab-paclitaxel than with solvent-based paclitaxel (24%; P<.001). Another subset analysis found that patients ages 70 years and older had improved overall survival (median 19.9 months) with nab-paclitaxel compared with solvent-based paclitaxel (median 10.4 months; P=.009). Patients in the nab-paclitaxel arm had less neuropathy, less hearing loss, and fewer interruptions in daily living than patients in the solvent-based paclitaxel arm.

Background: Bevacizumab is a monoclonal antibody against vascular endothelial growth factor. Severe pulmonary haemorrhage (PH) is a rare but serious potential adverse event associated with bevacizumab therapy for advanced non-squamous non-small-cell lung cancer (NSCLC)., Methods: A panel of expert oncologists, pulmonologists and radiologists reviewed the available data to identify predictive factors for PH in order to help guide physicians using bevacizumab in patients with NSCLC., Results: Patients with NSCLC are at an increased risk of PH owing to the underlying disease process. Patients with squamous histology and/or a history of grade ≥ 2 haemoptysis (≥ 2.5 ml per event) should not receive bevacizumab. No clinical or radiological features (including cavitation and central tumour location) reliably predict severe PH in bevacizumab-treated patients. Major blood vessel infiltration and bronchial vessel infiltration, encasement and abutting may predict PH; however, standardised radiological criteria for defining infiltration have not been established. Eligibility for bevacizumab is not affected by patient age, performance status or anticoagulation or antiplatelet therapy., Conclusions: An individualised risk-benefit assessment should be undertaken in all patients with NSCLC in whom bevacizumab is being considered. Further research is required to elucidate the mechanisms underlying PH and the clinical risk factors.

Introduction: Voreloxin is an anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, causing double-strand breaks in DNA, irreversible G2 arrest, and rapid onset of apoptosis. Based on preclinical activity of voreloxin in chemoresistant tumors, early phase I clinical activity, and a mechanism of action similar to other topoisomerase II inhibitors such as the anthracyclines and etoposide, this phase II trial was undertaken as second-line treatment of small cell lung cancer (SCLC)., Methods: Patients with extensive stage SCLC previously treated with one prior chemotherapy regimen were eligible. Patients with chemotherapy-sensitive or chemotherapy-refractory disease were considered as separate cohorts. Voreloxin (48 mg/m) was administered on the first day of each 21-day cycle for up to six cycles. The primary end point was objective response rate., Results: Fifty-five patients were enrolled including 28 with refractory SCLC and 27 with sensitive SCLC; 47 were evaluable for response. Three patients with sensitive SCLC had an objective response, including one complete response and two partial responses (11% response rate based on intent to treat). No patients in the refractory cohort had a response. The primary grade 3 toxicity was neutropenia., Conclusion: Voreloxin has minimal activity in relapsed SCLC when administered at 48 mg/m in a 3-week schedule.

Purpose: Somatic mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non-small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). The multicenter iTARGET trial prospectively examined first-line gefitinib in advanced NSCLC patients harboring EGFR mutations and explored the significance of EGFR mutation subtypes and TKI resistance mechanisms., Patients and Methods: Chemotherapy-naïve patients with advanced NSCLC with >or= 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate., Results: Ninety-eight patients underwent EGFR screening and mutations were detected in 34 (35%). EGFR mutations were primarily exon 19 deletions (53%) and L858R (26%) though 21% of mutation-positive cases had less common subtypes including exon 20 insertions, T790M/L858R, G719A, and L861Q. Thirty-one patients received gefitinib. The response rate was 55% (95% CI, 33 to 70) and median progression-free survival was 9.2 months (95% CI, 6.2 to 11.8). Therapy was well tolerated; 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients with classic activating mutations exhibited de novo gefitinib resistance and had concurrent genetic anomalies usually associated with acquired TKI resistance, specifically the T790M EGFR mutation and MET amplification., Conclusion: First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.

Background: This randomized phase II trial evaluated the efficacy and toxicity of oral topotecan compared with intravenous docetaxel in the second-line treatment of patients with non-small-cell lung cancer (NSCLC)., Patients and Methods: Eighty patients were randomized to receive topotecan (2 mg per day or 2.5 mg per day fixed dose for 5 of 7 days for 2 weeks) or docetaxel (75 mg/m2) every 21 days. Thirty-nine patients received 138 cycles of topotecan., Results: The overall response rate (RR; ORR) was 8%, median time to progression (TTP) was 1.6 months, median survival was 8.4 months, and the 1- and 2-year survival rates were 36% and 13%, respectively, for patients receiving topotecan. Forty-one patients were randomized, but only 38 patients were actually treated with 136 cycles of docetaxel. The ORR was 8% (7% intent to treat RR), median TTP was 1.4 months, median survival was 7.6 months, and the 1- and 2-year survival rates were 29% and 13%, respectively, for patients receiving docetaxel., Conclusion: Oral topotecan appears to be active and well tolerated when administered as a fixed dose daily for 5 of every 7 days for 2 weeks every 21 days and might provide another treatment alternative for patients with advanced-stage NSCLC.