Publications by authors named "Naiyer Rizvi"

116 Publications

Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non-Small-Cell Lung Cancer (MYSTIC).

Clin Lung Cancer 2021 Feb 19. Epub 2021 Feb 19.

Division of Hematology/Oncology, Columbia University Medical Center, New York, NY.

Background: The phase 3 MYSTIC study of durvalumab ± tremelimumab versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC) patients with tumor cell (TC) programmed cell death ligand 1 (PD-L1) expression ≥ 25% did not meet its primary endpoints. We report patient-reported outcomes (PROs).

Patients And Methods: Treatment-naïve patients were randomized (1:1:1) to durvalumab, durvalumab + tremelimumab, or chemotherapy. PROs were assessed in patients with PD-L1 TC ≥ 25% using EORTC Quality of Life Questionnaire (QLQ)-C30/LC13. Changes from baseline (12 months) for prespecified PRO endpoints of interest were analyzed by mixed model for repeated measures (MMRM) and time to deterioration (TTD) by stratified log-rank tests.

Results: There were no between-arm differences in baseline PROs (N = 488). Between-arm differences in MMRM-adjusted mean changes from baseline favored at least one of the durvalumab-containing arms versus chemotherapy (nominal P < .01) for C30 fatigue: durvalumab (-9.5; 99% confidence interval [CI], -17.0 to -2.0), durvalumab + tremelimumab (-11.7; 99% CI, -19.4 to -4.1); and for C30 appetite loss: durvalumab (-11.9; 99% CI, -21.1 to -2.7). TTD was longer with at least one of the durvalumab-containing arms versus chemotherapy (nominal P < .01) for global health status/quality of life: durvalumab (hazard ratio [HR] = 0.7; 95% CI, 0.5-1.0), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-1.0); and for physical functioning: durvalumab (HR = 0.6; 95% CI, 0.4-0.8), durvalumab + tremelimumab (HR = 0.6; 95% CI, 0.5-0.9) (both C30); as well as for the key symptoms of dyspnea: durvalumab (HR = 0.6; 95% CI, 0.5-0.9), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-1.0) (both LC13); fatigue: durvalumab + tremelimumab (HR = 0.6; 95% CI, 0.4-0.8); and appetite loss: durvalumab (HR = 0.5; 95% CI, 0.4-0.7), durvalumab + tremelimumab (HR = 0.7; 95% CI, 0.5-0.9) (both C30).

Conclusion: Durvalumab ± tremelimumab versus chemotherapy reduced symptom burden and improved TTD of PROs, suggesting it had no detrimental effects on quality of life in metastatic NSCLC patients.
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http://dx.doi.org/10.1016/j.cllc.2021.02.010DOI Listing
February 2021

Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial.

Lancet 2021 Feb;397(10274):592-604

Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA.

Background: We aimed to examine cemiplimab, a programmed cell death 1 inhibitor, in the first-line treatment of advanced non-small-cell lung cancer with programmed cell death ligand 1 (PD-L1) of at least 50%.

Methods: In EMPOWER-Lung 1, a multicentre, open-label, global, phase 3 study, eligible patients recruited in 138 clinics from 24 countries (aged ≥18 years with histologically or cytologically confirmed advanced non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1; never-smokers were ineligible) were randomly assigned (1:1) to cemiplimab 350 mg every 3 weeks or platinum-doublet chemotherapy. Crossover from chemotherapy to cemiplimab was allowed following disease progression. Primary endpoints were overall survival and progression-free survival per masked independent review committee. Primary endpoints were assessed in the intention-to-treat population and in a prespecified PD-L1 of at least 50% population (per US Food and Drug Administration request to the sponsor), which consisted of patients with PD-L1 of at least 50% per 22C3 assay done according to instructions for use. Adverse events were assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT03088540 and is ongoing.

Findings: Between June 27, 2017 and Feb 27, 2020, 710 patients were randomly assigned (intention-to-treat population). In the PD-L1 of at least 50% population, which consisted of 563 patients, median overall survival was not reached (95% CI 17·9-not evaluable) with cemiplimab (n=283) versus 14·2 months (11·2-17·5) with chemotherapy (n=280; hazard ratio [HR] 0·57 [0·42-0·77]; p=0·0002). Median progression-free survival was 8·2 months (6·1-8·8) with cemiplimab versus 5·7 months (4·5-6·2) with chemotherapy (HR 0·54 [0·43-0·68]; p<0·0001). Significant improvements in overall survival and progression-free survival were also observed with cemiplimab in the intention-to-treat population despite a high crossover rate (74%). Grade 3-4 treatment-emergent adverse events occurred in 98 (28%) of 355 patients treated with cemiplimab and 135 (39%) of 342 patients treated with chemotherapy.

Interpretation: Cemiplimab monotherapy significantly improved overall survival and progression-free survival compared with chemotherapy in patients with advanced non-small-cell lung cancer with PD-L1 of at least 50%, providing a potential new treatment option for this patient population.

Funding: Regeneron Pharmaceuticals and Sanofi.
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http://dx.doi.org/10.1016/S0140-6736(21)00228-2DOI Listing
February 2021

A Blood-based Assay for Assessment of Tumor Mutational Burden in First-line Metastatic NSCLC Treatment: Results from the MYSTIC Study.

Clin Cancer Res 2021 Mar 22;27(6):1631-1640. Epub 2020 Dec 22.

AstraZeneca, Gaithersburg, Maryland.

Purpose: Tumor mutational burden (TMB) has been shown to be predictive of survival benefit in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors. Measuring TMB in the blood (bTMB) using circulating cell-free tumor DNA (ctDNA) offers practical advantages compared with TMB measurement in tissue (tTMB); however, there is a need for validated assays and identification of optimal cutoffs. We describe the analytic validation of a new bTMB algorithm and its clinical utility using data from the phase III MYSTIC trial.

Patients And Methods: The dataset used for the clinical validation was from MYSTIC, which evaluated first-line durvalumab (anti-PD-L1 antibody) ± tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 antibody) or chemotherapy for metastatic NSCLC. bTMB and tTMB were evaluated using the GuardantOMNI and FoundationOne CDx assays, respectively. A Cox proportional hazards model and minimal value cross-validation approach were used to identify the optimal bTMB cutoff.

Results: In MYSTIC, somatic mutations could be detected in ctDNA extracted from plasma samples in a majority of patients, allowing subsequent calculation of bTMB. The success rate for obtaining valid TMB scores was higher for bTMB (809/1,001; 81%) than for tTMB (460/735; 63%). Minimal value cross-validation analysis confirmed the selection of bTMB ≥20 mutations per megabase (mut/Mb) as the optimal cutoff for clinical benefit with durvalumab + tremelimumab.

Conclusions: Our study demonstrates the feasibility, accuracy, and reproducibility of the GuardantOMNI ctDNA platform for quantifying bTMB from plasma samples. Using the new bTMB algorithm and an optimal bTMB cutoff of ≥20 mut/Mb, high bTMB was predictive of clinical benefit with durvalumab + tremelimumab versus chemotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3771DOI Listing
March 2021

Somatic HLA Class I Loss Is a Widespread Mechanism of Immune Evasion Which Refines the Use of Tumor Mutational Burden as a Biomarker of Checkpoint Inhibitor Response.

Cancer Discov 2021 Feb 30;11(2):282-292. Epub 2020 Oct 30.

Foundation Medicine, Inc., Cambridge, Massachusetts.

Neoantigen presentation arises as a result of tumor-specific mutations and is a critical component of immune surveillance that can be abrogated by somatic LOH of the human leukocyte antigen class I (HLA-I) locus. To understand the role of HLA-I LOH in oncogenesis and treatment, we utilized a pan-cancer genomic dataset of 83,644 patient samples, a small subset of which had treatment outcomes with immune checkpoint inhibitors (ICI). HLA-I LOH was common (17%) and unexpectedly had a nonlinear relationship with tumor mutational burden (TMB). HLA-I LOH was frequent at intermediate TMB, yet prevalence decreased above 30 mutations/megabase, suggesting highly mutated tumors require alternate immune evasion mechanisms. In ICI-treated patients with nonsquamous non-small cell lung cancer, HLA-I LOH was a significant negative predictor of overall survival. Survival prediction improved when combined with TMB, suggesting TMB with HLA-I LOH may better identify patients likely to benefit from ICIs. SIGNIFICANCE: This work shows the pan-cancer landscape of HLA-I LOH, revealing an unexpected "Goldilocks" relationship between HLA-I LOH and TMB, and demonstrates HLA-I LOH as a significant negative predictor of outcomes after ICI treatment. These data informed a combined predictor of outcomes after ICI and have implications for tumor vaccine development..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0672DOI Listing
February 2021

Safety and Clinical Activity of MEDI1873, a Novel GITR Agonist, in Advanced Solid Tumors.

Clin Cancer Res 2020 Dec 4;26(23):6196-6203. Epub 2020 Sep 4.

Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Purpose: The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor-related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors.

Patients And Methods: Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.

Results: Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug-antibody incidence was low. MEDI1873 increased peripheral CD4 effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks.

Conclusions: MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0452DOI Listing
December 2020

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world.

PLoS One 2020 3;15(9):e0238358. Epub 2020 Sep 3.

Division of Hematology and Oncology, Columbia University Medical Center, New York, NY, United States of America.

Background: Mutations in STK11 (STK11m) and frequently co-occurring KRAS mutations (KRASm/STK11m) are associated with poor survival in metastatic NSCLC (mNSCLC) immuno-oncology trials. There are limited data regarding the prognostic significance of these mutations in a real-world setting.

Methods: This retrospective cohort study analyzed de-identified electronic medical records from the Flatiron Clinico-Genomic database to identify patients with mNSCLC who had initiated first-line immunotherapy (IO; alone or in combination) or chemotherapy under routine care between January 1, 2013 and June 30, 2017. The primary objectives were to assess the prevalence of STK11m and KRASm/STK11m and to determine associations of these mutations with overall and progression-free survival (OS, PFS).

Results: Of 2407 patients with mNSCLC, STK11m and KRASm/STK11m were present in 13.6% and 6.5% of patients, respectively. Worse OS outcomes were observed in patients with STK11m versus STK11wt mNSCLC receiving IO (first-line, HR [95% CI], 1.4 [0.9-2.3; p = 0.1]; second-line [subset of first-line cohort], HR, 1.6 [1.3-2.0; p = 0.0002]) or chemotherapy (first-line, HR, 1.4 [1.2-1.6; p < 0.0001]); PFS outcomes showed similar trends. KRASm/STK11m double mutations were associated with worse OS and PFS outcomes versus KRASwt/STK11wt with IO and chemotherapy, similar to the single mutation (STK11m vs STK11wt) findings.

Conclusions: This large observational genomic study among patients receiving routine care highlights the negative prognostic impact of STK11m in patients with mNSCLC treated with IO or chemotherapy. These results complement previous clinical trial data and provide further evidence in the real world of a patient population that would benefit from new treatment options.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238358PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470384PMC
October 2020

Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors.

Clin Cancer Res 2020 Oct 14;26(20):5358-5367. Epub 2020 Aug 14.

UC San Diego Moores Cancer Center, La Jolla, California, USA.

Purpose: Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-in-human study evaluated MEDI0562 in adults with advanced solid tumors.

Patients And Methods: In this phase I, multicenter, open-label, single-arm, dose-escalation (3+3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.

Results: In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2-48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67 CD4 and CD8 memory T-cell proliferation in the periphery and decreased intratumoral OX40 FOXP3 cells.

Conclusions: MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3070DOI Listing
October 2020

Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: The phase II ATLANTIC study.

Lung Cancer 2020 09 30;147:137-142. Epub 2020 Jun 30.

Columbia University Medical Center, New York, NY, USA.

Introduction: In the phase II ATLANTIC study, durvalumab provided durable responses with acceptable tolerability in heavily pretreated patients with advanced NSCLC, across three independent patient cohorts defined by EGFR/ALK status and tumour PD-L1 expression. Preliminary overall survival (OS) data were encouraging. We now report final OS and updated safety data.

Methods: Patients with advanced NSCLC with disease progression following ≥2 previous systemic regimens received durvalumab 10 mg/kg every 2 weeks. The primary endpoint was objective response rate among patients with increased PD-L1 expression (defined as ≥25 % or ≥90 % of tumour cells [TCs], cohort-dependent). Secondary endpoints included OS and safety.

Results: 444 patients received durvalumab: 111 in Cohort 1 (EGFR+/ALK+), 265 in Cohort 2 (EGFR-/ALK-), and 68 in Cohort 3 (EGFR-/ALK-; TC ≥ 90 %). Median (95 % CI) OS was 13.3 months (6.3-24.5) in patients with EGFR+/ALK+ NSCLC with TC ≥ 25 %, 10.9 months (8.6-13.6) in patients with EGFR-/ALK- NSCLC with TC ≥ 25 %, and 13.2 months (5.9-not reached) in patients with EGFR-/ALK- NSCLC with TC ≥ 90 %. Median (95 % CI) OS was slightly shorter in patients with TC < 25 % (9.9 months [4.2-13.3] in patients with EGFR+/ALK+ NSCLC and 9.3 months [5.9-10.8] in those with EGFR-/ALK- NSCLC). Treatment-related adverse events of special interest occurred with similar incidences as reported previously.

Conclusions: After additional follow-up, final OS data remain encouraging across all cohorts, further supporting the clinical activity of durvalumab in patients with heavily pretreated advanced NSCLC, including those with EGFR+/ALK+ tumours. There were no new safety signals.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.032DOI Listing
September 2020

Characteristics and outcomes of lung cancer in solid organ transplant recipients.

Lung Cancer 2020 08 20;146:297-302. Epub 2020 Jun 20.

Columbia University Medical Center, Herbert Irving Pavilion, 161 Fort Washington Avenue, New York, NY 10032, United States; Department of Medicine, Columbia University Medical Center, United States. Electronic address:

Objectives: Lung cancer is the third most common malignancy that develops in patients following solid organ transplantation and is the leading cause of cancer deaths in the general population. The aims of this study are to examine the characteristics of patients who developed lung cancer following solid organ transplantation at our institution and to compare their outcomes to those of lung cancer patients without a history of transplant.

Materials And Methods: We performed a single-institution retrospective study of 44 solid organ transplant recipients who developed lung cancer and compared their characteristics to a cohort of 74 lung cancer patients without a history of transplant. We performed propensity score weighted analyses to compare outcomes between the two groups, including a cox proportional hazards model of overall survival.

Results: 52 % of post-transplant patients who developed lung cancer were diagnosed with stage III or IV disease. In the propensity score weighted analysis that accounted for age at diagnosis, sex, lung cancer stage at diagnosis, Charlson comorbidity index score, and ECOG performance score, post-transplant patients were more likely to have squamous cell histology (p < 0.01) and had worse overall survival compared to the non-transplant cohort (HR = 1.88, 95 % CI 1.13-3.12, p = 0.02). The difference in survival remained significant after accounting for differences in lung cancer histology and treatment (HR = 2.40, 95 % CI 1.27-3.78, p < 0.01).

Conclusions: When compared to non-transplant patients with lung cancer, post-transplant patients have worse overall survival after accounting for differences in age, sex, lung cancer stage, comorbidities, and performance status. This survival difference is not solely attributable to differences in tumor histology and treatments received. This may suggest that post-transplant malignancies are more aggressive and difficult to treat.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.018DOI Listing
August 2020

Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.

Lancet Oncol 2020 06 7;21(6):786-795. Epub 2020 May 7.

Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. Electronic address:

Background: Approximately 25% of all patients with non-small-cell lung cancer present with resectable stage IB-IIIA disease, and although perioperative chemotherapy is the standard of care, this treatment strategy provides only modest survival benefits. On the basis of the activity of immune checkpoint inhibitors in metastatic non-small-cell lung cancer, we designed a trial to test the activity of the PD-L1 inhibitor, atezolizumab, with carboplatin and nab-paclitaxel given as neoadjuvant treatment before surgical resection.

Methods: This open-label, multicentre, single-arm, phase 2 trial was done at three hospitals in the USA. Eligible patients were aged 18 years or older and had resectable American Joint Committee on Cancer-defined stage IB-IIIA non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1, and a history of smoking exposure. Patients received neoadjuvant treatment with intravenous atezolizumab (1200 mg) on day 1, nab-paclitaxel (100 mg/m) on days 1, 8, and 15, and carboplatin (area under the curve 5; 5 mg/mL per min) on day 1, of each 21-day cycle. Patients without disease progression after two cycles proceeded to receive two further cycles, which were then followed by surgical resection. The primary endpoint was major pathological response, defined as the presence of 10% or less residual viable tumour at the time of surgery. All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT02716038, and is ongoing but no longer recruiting participants.

Findings: Between May 26, 2016, and March 1, 2019, we assessed 39 patients for eligibility, of whom 30 patients were enrolled. 23 (77%) of these patients had stage IIIA disease. 29 (97%) patients were taken into the operating theatre, and 26 (87%) underwent successful R0 resection. At the data cutoff (Aug 7, 2019), the median follow-up period was 12·9 months (IQR 6·2-22·9). 17 (57%; 95% CI 37-75) of 30 patients had a major pathological response. The most common treatment-related grade 3-4 adverse events were neutropenia (15 [50%] of 30 patients), increased alanine aminotransferase concentrations (two [7%] patients), increased aspartate aminotransferase concentration (two [7%] patients), and thrombocytopenia (two [7%] patients). Serious treatment-related adverse events included one (3%) patient with grade 3 febrile neutropenia, one (3%) patient with grade 4 hyperglycaemia, and one (3%) patient with grade 2 bronchopulmonary haemorrhage. There were no treatment-related deaths.

Interpretation: Atezolizumab plus carboplatin and nab-paclitaxel could be a potential neoadjuvant regimen for resectable non-small-cell lung cancer, with a high proportion of patients achieving a major pathological response, and manageable treatment-related toxic effects, which did not compromise surgical resection.

Funding: Genentech and Celgene.
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http://dx.doi.org/10.1016/S1470-2045(20)30140-6DOI Listing
June 2020

Beyond Tumor PD-L1: Emerging Genomic Biomarkers for Checkpoint Inhibitor Immunotherapy.

Am Soc Clin Oncol Educ Book 2020 Mar;40:1-11

Columbia University Medical Center, New York, NY.

Despite the success of immune checkpoint blockade as a strategy for activating an antitumor immune response and promoting cancer regression, only a subset of patients have durable clinical benefit. Efforts are ongoing to identify robust biomarkers that can effectively predict treatment response to immune checkpoint inhibitors (ICIs). Although PD-L1 expression is useful for stratifying patients, it is an imperfect tool. Comprehensive next-generation sequencing platforms that are readily used in clinical practice to identify a tumor's potentially actionable genetic alterations also reveal tumor genomic features, including tumor mutation burden (TMB), that may impact the response to ICIs. High TMB enhances tumor immunogenicity through increased numbers of tumor neoantigens that may promote an immune response. Defective DNA repair, leading to microsatellite instability, is an endogenous mechanism for increased tumor TMB that augments response to anti-PD-1 blockade. Alternatively, DNA damage from exogenous factors is responsible for high TMB seen in melanoma, lung cancer, and urothelial carcinoma, among tumor subtypes with higher response rates to ICIs. In this review, we summarize data supporting the use of TMB as a biomarker as well as its known limitations. We also highlight specific tumor suppressor genes and oncogenes that are under investigation as biomarkers for ICI response and resistance. Efforts are ongoing to delineate which genomic tumor characteristics can eventually be utilized in clinical practice to ascertain the benefit of ICIs for an individual patient.
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http://dx.doi.org/10.1200/EDBK_289967DOI Listing
March 2020

Challenges in lung cancer therapy during the COVID-19 pandemic.

Lancet Respir Med 2020 06 9;8(6):542-544. Epub 2020 Apr 9.

Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, 53100 Siena, Italy; NIBIT Foundation Onlus, Siena, Italy. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(20)30170-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146673PMC
June 2020

Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial.

JAMA Oncol 2020 05;6(5):661-674

Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland.

Importance: Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer.

Objective: To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer.

Design, Setting, And Participants: This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018.

Interventions: Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy.

Main Outcomes And Measures: The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory.

Results: Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively.

Conclusions And Relevance: The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab.

Trial Registration: ClinicalT rials.gov Identifier: NCT02453282.
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http://dx.doi.org/10.1001/jamaoncol.2020.0237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146551PMC
May 2020

Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project.

J Immunother Cancer 2020 03;8(1)

Quality in Pathology (QuIP), Berlin, Germany.

Background: Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, demonstrates predictive biomarker potential for the identification of patients with cancer most likely to respond to immune checkpoint inhibitors. TMB is optimally calculated by whole exome sequencing (WES), but next-generation sequencing targeted panels provide TMB estimates in a time-effective and cost-effective manner. However, differences in panel size and gene coverage, in addition to the underlying bioinformatics pipelines, are known drivers of variability in TMB estimates across laboratories. By directly comparing panel-based TMB estimates from participating laboratories, this study aims to characterize the theoretical variability of panel-based TMB estimates, and provides guidelines on TMB reporting, analytic validation requirements and reference standard alignment in order to maintain consistency of TMB estimation across platforms.

Methods: Eleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB). A reference TMB value was calculated from the entire exome using a uniform bioinformatics pipeline all members agreed on (WES TMB). Linear regression analyses were performed to investigate the relationship between WES and panel TMB for all 32 cancer types combined and separately. Variability in panel TMB values at various WES TMB values was also quantified using 95% prediction limits.

Results: Study results demonstrated that variability within and between panel TMB values increases as the WES TMB values increase. For each panel, prediction limits based on linear regression analyses that modeled panel TMB as a function of WES TMB were calculated and found to approximately capture the intended 95% of observed panel TMB values. Certain cancer types, such as uterine, bladder and colon cancers exhibited greater variability in panel TMB values, compared with lung and head and neck cancers.

Conclusions: Increasing uptake of TMB as a predictive biomarker in the clinic creates an urgent need to bring stakeholders together to agree on the harmonization of key aspects of panel-based TMB estimation, such as the standardization of TMB reporting, standardization of analytical validation studies and the alignment of panel-based TMB values with a reference standard. These harmonization efforts should improve consistency and reliability of panel TMB estimates and aid in clinical decision-making.
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http://dx.doi.org/10.1136/jitc-2019-000147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174078PMC
March 2020

Synchronous Pulmonary Adenocarcinomas.

Am J Clin Pathol 2020 06;154(1):57-69

Department of Pathology and Cell Biology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, NY.

Objectives: To determine concordance/discordance between morphology and molecular testing (MT) among synchronous pulmonary carcinomas using targeted next generation sequencing (NGS), with and without comprehensive molecular review (CMR), vs analyses of multiple singe genes (non-NGS).

Methods: Results of morphologic and MT assessment were classified as concordant, discordant, or indeterminate. For discordant cases, comprehensive histologic assessment (CHA) was performed.

Results: Forty-seven cases with 108 synchronous tumors were identified and underwent MT (NGS, n = 23 and non-NGS, n = 24). Histology and MT were concordant, discordant, and indeterminate in 53% (25/47), 21% (10/47), and 26% (12/47) of cases, respectively. CHA of the 10 discordant cases revised results of three cases.

Conclusions: There is discordance between histology and MT in a subset of cases and MT provides an objective surrogate for staging synchronous tumors. A limited gene panel is sufficient for objectively assessing a relationship if the driver mutations are distinct. Relatedness of mutations require CMR with a larger NGS panel (eg, 50 genes).
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http://dx.doi.org/10.1093/ajcp/aqaa023DOI Listing
June 2020

Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy.

Nat Med 2019 11 7;25(11):1715-1720. Epub 2019 Nov 7.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Functional diversity of the highly polymorphic human leukocyte antigen class I (HLA-I) genes underlies successful immunologic control of both infectious disease and cancer. The divergent allele advantage hypothesis dictates that an HLA-I genotype with two alleles with sequences that are more divergent enables presentation of more diverse immunopeptidomes. However, the effect of sequence divergence between HLA-I alleles-a quantifiable measure of HLA-I evolution-on the efficacy of immune checkpoint inhibitor (ICI) treatment for cancer remains unknown. In the present study the germline HLA-I evolutionary divergence (HED) of patients with cancer treated with ICIs was determined by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient's genotype. HED was a strong determinant of survival after treatment with ICIs. Even among patients fully heterozygous at HLA-I, patients with an HED in the upper quartile respond better to ICIs than patients with a low HED. Furthermore, HED strongly impacts the diversity of tumor, viral and self-immunopeptidomes and intratumoral T cell receptor clonality. Similar to tumor mutation burden, HED is a fundamental metric of diversity at the major histocompatibility complex-peptide complex, which dictates ICI efficacy. The data link divergent HLA allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of HLA-mediated immunity.
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http://dx.doi.org/10.1038/s41591-019-0639-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938381PMC
November 2019

Prognostic Significance of Liver Metastasis in Durvalumab-Treated Lung Cancer Patients.

Clin Lung Cancer 2019 11 26;20(6):e601-e608. Epub 2019 Jun 26.

AstraZeneca, Gaithersburg, MD.

Introduction: Two clinical studies (Study 1108 and ATLANTIC) were analyzed to evaluate the prognostic value of baseline liver metastases (LMs) in advanced/metastatic non-small-cell lung cancer patients treated with durvalumab 10 mg/kg every 2 weeks.

Patients And Methods: A multivariate Cox proportional hazards analysis was conducted; covariates included performance status, tumor stage, histology, sex, age, smoking status, and programmed cell death ligand 1 (PD-L1) status.

Results: In all, 569 patients were included. LMs were present in 31.6% (96/304) of Study 1108 patients and 17.9% (47/263) of ATLANTIC patients. Median overall survival (OS) was shorter in patients with LMs than in those without in both studies. In both studies, LMs were an independent negative prognostic factor for OS and progression-free survival. Objective response rates were also significantly lower. PD-L1 independently predicted benefit across all patients.

Conclusion: Liver metastases were associated with worse outcomes irrespective of PD-L1 status, but PD-L1 status predicted benefit from durvalumab irrespective of LMs.
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http://dx.doi.org/10.1016/j.cllc.2019.06.020DOI Listing
November 2019

Treatment Outcomes of Immune-Related Cutaneous Adverse Events.

J Clin Oncol 2019 10 19;37(30):2746-2758. Epub 2019 Jun 19.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics.

Methods: A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed.

Results: A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype ( = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 0.71; < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; = .043).

Conclusion: Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.
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http://dx.doi.org/10.1200/JCO.18.02141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001790PMC
October 2019

Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study.

J Clin Oncol 2019 10 2;37(28):2518-2527. Epub 2019 Jun 2.

Westmead Hospital, University of Sydney, Sydney, NSW, Australia.

Purpose: Pembrolizumab monotherapy has demonstrated durable antitumor activity in advanced programmed death ligand 1 (PD-L1)-expressing nonsmall-cell lung cancer (NSCLC). We report 5-year outcomes from the phase Ib KEYNOTE-001 study. These data provide the longest efficacy and safety follow-up for patients with NSCLC treated with pembrolizumab monotherapy.

Patients And Methods: Eligible patients had confirmed locally advanced/metastatic NSCLC and provided a contemporaneous tumor sample for PD-L1 evaluation by immunohistochemistry using the 22C3 antibody. Patients received intravenous pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. Investigators assessed response per immune-related response criteria. The primary efficacy end point was objective response rate. Overall survival (OS) and duration of response were secondary end points.

Results: We enrolled 101 treatment-naive and 449 previously treated patients. Median follow-up was 60.6 months (range, 51.8 to 77.9 months). At data cutoff-November 5, 2018-450 patients (82%) had died. Median OS was 22.3 months (95% CI, 17.1 to 32.3 months) in treatment-naive patients and 10.5 months (95% CI, 8.6 to 13.2 months) in previously treated patients. Estimated 5-year OS was 23.2% for treatment-naive patients and 15.5% for previously treated patients. In patients with a PD-L1 tumor proportion score of 50% or greater, 5-year OS was 29.6% and 25.0% in treatment-naive and previously treated patients, respectively. Compared with analysis at 3 years, only three new-onset treatment-related grade 3 adverse events occurred (hypertension, glucose intolerance, and hypersensitivity reaction, all resolved). No late-onset grade 4 or 5 treatment-related adverse events occurred.

Conclusion: Pembrolizumab monotherapy provided durable antitumor activity and high 5-year OS rates in patients with treatment-naive or previously treated advanced NSCLC. Of note, the 5-year OS rate exceeded 25% among patients with a PD-L1 tumor proportion score of 50% or greater. Pembrolizumab had a tolerable long-term safety profile with little evidence of late-onset or new toxicity.
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http://dx.doi.org/10.1200/JCO.19.00934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768611PMC
October 2019

Management Strategies for Early-Onset Pulmonary Events Associated with Brigatinib.

J Thorac Oncol 2019 09 18;14(9):1547-1555. Epub 2019 May 18.

University of California San Diego, Moores Cancer Center, La Jolla, California.

Introduction: Rare cases of early-onset pulmonary events (EOPEs) occurring within days of the start of administration of brigatinib have been reported (incidence 3%-6% with use of the recommended dose of 90 mg for 7 days and then a 180-mg step-up dosing regimen). Current prescribing information suggests dose interruption and then dose reduction for grade 1 or 2 events and discontinuation for recurrent or higher grade events. However, clinical experience suggests that alternative strategies exist to safely maintain dosing.

Methods: Case vignettes illustrating different EOPE clinical scenarios were assembled; they included (1) successful treatment through the initial EOPE, (2) successful rechallenge after the EOPE, (3) successful rechallenge after the EOPE with utilization of a shallower step-up regimen, and (4) unsuccessful rechallenge.

Results: Rapid tolerization to EOPEs within 5 to 8 days may occur with continued dosing, suggesting that dose interruption could be avoided with close observation and temporary supportive care (including supplemental oxygen). If dose interruption occurs, restarting administration of brigatinib at 30 mg, followed by dose increases in 30-mg increments every 3 days to the full dose as tolerated ("shallow step-up dosing") may maximize safety during rechallenge. As compromised baseline respiratory function may increase the rate of clinically apparent EOPEs, proactive use of shallow step-up dosing could be considered in select cases.

Conclusions: Clinically apparent EOPEs are a rare complication of brigatinib. They occur within days of starting administration of the drug, with rapid tolerization possible during continued dosing. Adapting the EOPE nomenclature to include the word transient (TEOPE) may further clinician and patient understanding in distinguishing these events from the pneumonitis seen with other tyrosine kinase inhibitors. Improved education and appropriate supportive care and dosing should allow more patients to maximally and safely benefit from brigatinib.
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http://dx.doi.org/10.1016/j.jtho.2019.04.028DOI Listing
September 2019

Impact of Patient Characteristics, Prior Therapy, and Sample Type on Tumor Cell Programmed Cell Death Ligand 1 Expression in Patients with Advanced NSCLC Screened for the ATLANTIC Study.

J Thorac Oncol 2019 08 4;14(8):1390-1399. Epub 2019 May 4.

Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.

Introduction: We evaluated the impact of patient characteristics, sample types, and prior non-immunotherapy treatment on tumor cell (TC) programmed cell death ligand 1 (PD-L1) expression using samples from patients with advanced NSCLC.

Methods: Patients (N = 1590) screened for the ATLANTIC study submitted a recently acquired (≤3 months) or archival (>3 months to >3 years old) tumor sample for PD-L1 assessment using the VENTANA PD-L1 (SP263) Assay with a cutoff of ≥25% of TCs expressing PD-L1 (TC ≥25%). Samples were acquired either before or after the two or more treatment regimens required for study entry and sample age varied among patients. A subset of patients (n = 123) provided both recent and archival samples.

Results: A total of 517 of 1590 (32.5%) patients had TC greater than or equal to 25%: prevalence was greater in smokers versus nonsmokers (p = 0.0005) and those with EGFR- versus EGFR+ tumors (p = 0.0002); these effects were independent. Prevalence of TC greater than or equal to 25% was increased in recent metastatic versus primary (p = 0.005) and recent versus archival (p = 0.039) samples. Chemotherapy or radiotherapy, but not tyrosine kinase inhibition, before sampling was associated with significantly increased PD-L1 prevalence. PD-L1 status (TC ≥25% cutoff) remained unchanged in 74.0% of patients with recent and archival samples; where PD-L1 status changed, it was more likely to increase than decrease over time or with intervening treatment.

Conclusions: Several factors potentially impact PD-L1 TC greater than or equal to 25% prevalence in advanced NSCLC; however, no characteristic can be considered a surrogate for PD-L1 expression. Fresh biopsy may provide more accurate assessment of current tumoral PD-L1 expression where a low/negative result is seen in an archival sample, especially if the patient has received intervening therapy.
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http://dx.doi.org/10.1016/j.jtho.2019.04.025DOI Listing
August 2019

Managing Pulmonary Toxicities Associated with Immunotherapy: A Case Discussion.

Oncologist 2019 06 21;24(6):730-734. Epub 2019 Mar 21.

Columbia University Medical Center, New York New York, USA

Immunotherapy has changed the field of oncology around the world with the approval of immune checkpoint inhibitors for a number of tumor types over the last 5 years. However, immune-mediated adverse events can be challenging and difficult to treat, with one of the most dire consequences being immune-mediated pneumonitis. KEY POINTS: Rapid intervention and aggressive management for grade 3 or greater pneumonitisSlow taper of steroids and also recommend pneumocystis carinii pneumonia prophylaxisMonitor carefully for a pneumonitis flare with steroid taper, which can occur in the absence of resuming anti-programmed cell death protein 1 (PD-1) [1], and do not resume anti-PD-1 therapy until completely off steroids and no clinical or radiologic evidence of recurrenceConsider observation without anti-PD-1 resumption-in this case, durable response was maintained even without resuming anti-PD-1 therapy.
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http://dx.doi.org/10.1634/theoncologist.2018-0241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656522PMC
June 2019

Tumor mutational load predicts survival after immunotherapy across multiple cancer types.

Nat Genet 2019 02 14;51(2):202-206. Epub 2019 Jan 14.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.
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http://dx.doi.org/10.1038/s41588-018-0312-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365097PMC
February 2019

Deep learning using tumor HLA peptide mass spectrometry datasets improves neoantigen identification.

Nat Biotechnol 2018 Dec 17. Epub 2018 Dec 17.

Virginia Cancer Specialists, Fairfax, Virginia, USA.

Neoantigens, which are expressed on tumor cells, are one of the main targets of an effective antitumor T-cell response. Cancer immunotherapies to target neoantigens are of growing interest and are in early human trials, but methods to identify neoantigens either require invasive or difficult-to-obtain clinical specimens, require the screening of hundreds to thousands of synthetic peptides or tandem minigenes, or are only relevant to specific human leukocyte antigen (HLA) alleles. We apply deep learning to a large (N = 74 patients) HLA peptide and genomic dataset from various human tumors to create a computational model of antigen presentation for neoantigen prediction. We show that our model, named EDGE, increases the positive predictive value of HLA antigen prediction by up to ninefold. We apply EDGE to enable identification of neoantigens and neoantigen-reactive T cells using routine clinical specimens and small numbers of synthetic peptides for most common HLA alleles. EDGE could enable an improved ability to develop neoantigen-targeted immunotherapies for cancer patients.
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http://dx.doi.org/10.1038/nbt.4313DOI Listing
December 2018

Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1).

Proc Natl Acad Sci U S A 2018 10 8;115(43):E10119-E10126. Epub 2018 Oct 8.

Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080.

Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-γ-induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti-PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.
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http://dx.doi.org/10.1073/pnas.1802166115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205493PMC
October 2018

Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer.

J Thorac Oncol 2018 Dec 27;13(12):1818-1831. Epub 2018 Sep 27.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development. To achieve more rapid knowledge turns, study designs, endpoints, and definitions of pathologic response should be standardized and harmonized. Continued dialogue with all stakeholders will be critical to design and test novel induction strategies, which could expedite drug development for patients with early lung cancer who are at high risk for metastatic recurrence.
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http://dx.doi.org/10.1016/j.jtho.2018.09.017DOI Listing
December 2018

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC).

J Immunother Cancer 2018 07 17;6(1):75. Epub 2018 Jul 17.

Yale Comprehensive Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW221, New Haven, CT, 06520-8028, USA.

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of all cases. Until recently, chemotherapy - characterized by some benefit but only rare durable responses - was the only treatment option for patients with NSCLC whose tumors lacked targetable mutations. By contrast, immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC. Three immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab, are now approved for use in first- and/or second-line settings for selected patients with advanced NSCLC, with promising benefit also seen in patients with stage III NSCLC. Additionally, durvalumab following chemoradiation has been approved for use in patients with locally advanced disease. Due to the distinct features of cancer immunotherapy, and rapid progress in the field, clinical guidance is needed on the use of these agents, including appropriate patient selection, sequencing of therapies, response monitoring, adverse event management, and biomarker testing. The Society for Immunotherapy of Cancer (SITC) convened an expert Task Force charged with developing consensus recommendations on these key issues. Following a systematic process as outlined by the National Academy of Medicine, a literature search and panel voting were used to rate the strength of evidence for each recommendation. This consensus statement provides evidence-based recommendations to help clinicians integrate immune checkpoint inhibitors into the treatment plan for patients with NSCLC. This guidance will be updated following relevant advances in the field.
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http://dx.doi.org/10.1186/s40425-018-0382-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048854PMC
July 2018

Nivolumab Plus Erlotinib in Patients With EGFR-Mutant Advanced NSCLC.

J Thorac Oncol 2018 09 23;13(9):1363-1372. Epub 2018 May 23.

Memorial Sloan Kettering Cancer Center, New York, New York.

Introduction: This phase I study evaluated nivolumab combined with erlotinib in patients with advanced EGFR-mutant NSCLC.

Methods: Patients with advanced EGFR-mutant NSCLC who were EGFR tyrosine kinase inhibitor (TKI)-naive or TKI-treated but had not received chemotherapy were treated with nivolumab 3 mg/kg every 2 weeks and erlotinib 150 mg/d until disease progression or unacceptable toxicity. The primary objective was safety and tolerability.

Results: Twenty patients with TKI-treated and one with TKI-naive EGFR-mutant NSCLC were treated with nivolumab plus erlotinib. Treatment-related grade 3 toxicities occurred in five patients (liver enzyme elevations, n = 2; diarrhea, n = 2; weight loss, n = 1), with no grade ≥4 toxicities. In the TKI-treated population, the objective response rate was 15% (3 of 20, including one complete response), and the 24-week progression-free survival rate was 48%. Responses lasted 13.8, 17.6, and 38.2 months per investigator records. A fourth patient had a nonconventional immune-related response lasting 12.5 months. Among these four patients, two were never-smokers and one each had 35- and <1-pack-year histories. Post-EGFR TKI pre-trial tumor biopsy specimens from these patients detected EGFR T790M mutations in two patients and MNNG HOS Transforming gene (MET) amplification in a third; two patients each had primary EGFR exon 19 deletions or L858R mutations. The TKI-naive patient, who had compound EGFR mutations (L858R and S768I) and ultimately achieved a complete response, had an ongoing response lasting more than 5 years based on investigator records.

Conclusions: Nivolumab plus erlotinib was tolerable, with durable responses in patients with EGFR-mutant, TKI-treated NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2018.05.015DOI Listing
September 2018

FIR: Efficacy, Safety, and Biomarker Analysis of a Phase II Open-Label Study of Atezolizumab in PD-L1-Selected Patients With NSCLC.

J Thorac Oncol 2018 11;13(11):1733-1742

Columbia University, New York, New York.

Introduction: The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti-programmed death-ligand 1 (PD-L1) atezolizumab in advanced NSCLC selected by tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression.

Methods: Patients with PD-L1 TC2/3 (PD-L1 staining on ≥5% of TC) or IC2/3 tumors (PD-L1 staining on ≥5% of IC; determined by SP142 PD-L1 immunohistochemistry assay) with paired fresh and archival histology samples were recruited into cohort 1 (chemotherapy-naive/>6 months between adjuvant chemotherapy and recurrence), cohort 2 (≥ second-line without brain metastases), or cohort 3 (≥ second-line with treated brain metastases). Patients received 1200 mg atezolizumab on day 1 (21-day cycles). Primary endpoint was investigator-assessed modified Response Evaluation Criteria in Solid Tumors, objective response rate (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints were overall survival, progression-free survival, duration of response, and safety.

Results: Patients (N = 138) were enrolled (137 evaluable for response: cohort 1, n = 31; cohort 2, n = 93; and cohort 3, n = 13). Investigator-assessed objective response rate was 32%, 21%, and 23% for cohorts 1, 2, and 3, respectively. Treatment-related adverse events were reported in 81%, 67%, and 69% of patients, respectively, including grade 3-4 treatment-related adverse events in 16%, 19%, and 15%, respectively. Moreover, 88.6% (86 of 97) paired baseline tumor samples had <5% change in TC/IC PD-L1 expression over time.

Conclusions: Atezolizumab monotherapy showed clinical activity in patients with NSCLC, including those with brain metastases; safety was consistent with previous trials. Atezolizumab has completed phase III monotherapy studies in second-line. Front-line trials are ongoing, confirming these favorable results.
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http://dx.doi.org/10.1016/j.jtho.2018.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455890PMC
November 2018