Publications by authors named "Scott Gettinger"

111 Publications

Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer: The Lung-MAP S1400I Phase 3 Randomized Clinical Trial.

JAMA Oncol 2021 Jul 15. Epub 2021 Jul 15.

Yale Cancer Center, New Haven, Connecticut.

Importance: Nivolumab plus ipilimumab is superior to platinum-based chemotherapy in treatment-naive advanced non-small cell lung cancer (NSCLC). Nivolumab is superior to docetaxel in advanced pretreated NSCLC.

Objective: To determine whether the addition of ipilimumab to nivolumab improves survival in patients with advanced, pretreated, immunotherapy-naive squamous (Sq) NSCLC.

Design, Setting, And Participants: The Lung Cancer Master Protocol (Lung-MAP) S1400I phase 3, open-label randomized clinical trial was conducted from December 18, 2015, to April 23, 2018, randomizing patients in a 1:1 ratio to nivolumab alone or combined with ipilimumab. The median follow-up in surviving patients was 29.5 months. The trial was conducted through the National Clinical Trials Network and included patients with advanced immunotherapy-naive SqNSCLC and a Zubrod score of 0 (asymptomatic) to 1 (symptomatic but completely ambulatory) with disease progression after standard platinum-based chemotherapy. Randomization was stratified by sex and number of prior therapies (1 vs 2 or more). Data were analyzed from May 3, 2018, to February 1, 2021.

Interventions: Nivolumab, 3 mg/kg intravenously every 2 weeks, with or without ipilimumab, 1 mg/kg intravenously every 6 weeks, until disease progression or intolerable toxic effects.

Main Outcomes And Measures: The primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (IA-PFS) and response per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1.

Results: Of 275 enrolled patients, 252 (mean age, 67.5 years [range 41.8-90.3 years]; 169 men [67%]; 206 White patients [82%]) were deemed eligible (125 randomized to nivolumab/ipilimumab and 127 to nivolumab). The study was closed for futility at a planned interim analysis. Overall survival was not significantly different between the groups (hazard ratio [HR], 0.87; 95% CI, 0.66-1.16; P = .34). Median survival was 10 months (95% CI, 8.0-14.4 months) in the nivolumab/ipilimumab group and 11 months (95% CI, 8.6-13.7 months) in the nivolumab group. The IA-PFS HR was 0.80 (95% CI, 0.61-1.03; P = .09); median IA-PFS was 3.8 months (95% CI, 2.7-4.4 months) in the nivolumab/ipilimumab group and 2.9 months (95% CI, 1.8-4.0 months) in the nivolumab alone group. Response rates were 18% (95% CI, 12%-25%) with nivolumab/ipilimumab and 17% (95% CI, 10%-23%) with nivolumab. Median response duration was 28.4 months (95% CI, 4.9 months to not reached) with nivolumab/ipilimumab and 9.7 months with nivolumab (95% CI, 4.2-23.1 months). Grade 3 or higher treatment-related adverse events occurred in 49 of 124 patients (39.5%) who received nivolumab/ipilimumab and in 41 of 123 (33.3%) who received nivolumab alone. Toxic effects led to discontinuation in 31 of 124 patients (25%) on nivolumab/ipilimumab and in 19 of 123 (15%) on nivolumab.

Conclusions And Relevance: In this phase 3 randomized clinical trial, ipilimumab added to nivolumab did not improve outcomes in patients with advanced, pretreated, immune checkpoint inhibitor-naive SqNSCLC.

Trial Registration: ClinicalTrials.gov Identifier: NCT02785952.
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http://dx.doi.org/10.1001/jamaoncol.2021.2209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283667PMC
July 2021

Tumor DNA Mutations From Intraparenchymal Brain Metastases Are Detectable in CSF.

JCO Precis Oncol 2021 12;5. Epub 2021 Jan 12.

Department of Neurosurgery, Yale University, New Haven, CT.

Discordant responses between brain metastases and extracranial tumors can arise from branched tumor evolution, underscoring the importance of profiling mutations to optimize therapy. However, the morbidity of brain biopsies limits their use. We investigated whether cell-free DNA (cfDNA) in CSF could serve as an effective surrogate marker for genomic profiling of intraparenchymal (IP) brain metastases.

Methods: CSF and blood were collected simultaneously from patients with progressive brain metastases undergoing a craniotomy or lumbar puncture. Mutations in both biofluids were measured using an error-suppressed deep sequencing method previously published by our group. Forty-three regions of 24 cancer-associated genes were assayed.

Results: This study enrolled 14 patients with either IP brain metastases (n = 12) or cytology-positive leptomeningeal disease (LMD, n = 2) and two controls with normal pressure hydrocephalus. Primary cancer types were lung, melanoma, renal cell, and colorectal. cfDNA was measurable in all sixteen samples of CSF. Cancer-associated mutations were found in the CSF of ten patients (eight with IP [67%] and two with LMD [100%]) and plasma of five patients (five with IP [42%] and none with LMD). All patients with plasma cfDNA had extracranial tumors. Among the five patients in the cohort who also had mutation data from time-matched brain metastasis tissue, four patients (80%) had matching mutations detected in CSF and brain, whereas only one patient (20%) had matching mutations detected in plasma and brain.

Conclusion: The detection of mutational DNA in CSF is not restricted to LMD and was found in two thirds of patients with IP brain metastases in our cohort. Analysis of CSF can be a viable alternative to biopsy for detection of somatic mutations in brain metastases.
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http://dx.doi.org/10.1200/PO.20.00292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232069PMC
January 2021

A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non-Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1.

Clin Cancer Res 2021 Jun 17. Epub 2021 Jun 17.

Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut.

Purpose: PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges.

Patients And Methods: We conducted a phase I trial of CD40 agonist APX005M (sotigalimab) and CSF1R inhibitor cabiralizumab with or without nivolumab using a 3+3 dose-escalation design (NCT03502330). Patients were enrolled from June 2018 to April 2019. Eligibility included patients with biopsy-proven advanced melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) who progressed on anti-PD-1/PD-L1. APX005M was dose escalated (0.03, 0.1, or 0.3 mg/kg i.v.) with a fixed dose of cabiralizumab with or without nivolumab every 2 weeks until disease progression or intolerable toxicity.

Results: Twenty-six patients (12 melanoma, 1 NSCLC, and 13 RCC) were enrolled in six cohorts, 17 on nivolumab-containing regimens. Median duration of follow-up was 21.3 months. The most common treatment-related adverse events were asymptomatic elevations of lactate dehydrogenase ( = 26), creatine kinase ( = 25), aspartate aminotransferase ( = 25), and alanine aminotransferase ( = 19); periorbital edema ( = 17); and fatigue ( = 13). One dose-limiting toxicity (acute respiratory distress syndrome) occurred in cohort 2. The recommended phase 2 dose was APX005M 0.3 mg/kg, cabiralizumab 4 mg/kg, and nivolumab 240 mg every 2 weeks. Median days on treatment were 66 (range, 23-443). Median cycles were 4.5 (range, 2-21). One patient had unconfirmed partial response (4%), 8 stable disease (31%), 16 disease progression (62%), and 1 unevaluable (4%). Pro-inflammatory cytokines were upregulated 4 hours post-infusion. CD40 and MCSF increased after therapy.

Conclusions: This first in-human study of patients with anti-PD-1/PD-L1-resistant tumors treated with dual macrophage-polarizing therapy, with or without nivolumab demonstrated safety and pharmacodynamic activity. Optimization of the dosing frequency and sequence of this combination is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0903DOI Listing
June 2021

Clinical characteristics and outcomes of splenic infarction in cancer patients: a retrospective, single center report of 206 cases.

J Thromb Thrombolysis 2021 Mar 25. Epub 2021 Mar 25.

Department of Internal Medicine, Section of Hematology, Yale University School of Medicine, 333 Cedar Street, PO Box 208028, New Haven, CT, 06520-8028, USA.

Cancer patients have a high risk of thromboembolic events including splenic infarct (SI). However, risk factors for SI in cancer patients are poorly understood, and the utility of systemic anticoagulation in such patients is uncertain. We performed a retrospective cohort study of all cancer patients with SI treated at Yale New Haven Hospital from 2008 to 2017. Central review of radiology imaging was performed to confirm the diagnosis of SI. Baseline differences in variables among patients with and without recurrent SI were compared using Fisher's exact test, Pearson's χ test, and t-test. Multivariable regression models were conducted to identify factors associated with recurrent SI. Of 206 patients with cancer and SI, 42 had a prior venous thromboembolic event, while 29 had atrial fibrillation/flutter. At a median follow-up of 11.4 months (range: 0-142.3 months), 152 patients underwent follow-up imaging, with only 6 having recurrent SI. The use of anticoagulation after initial SI was associated with a nonsignificant increase in recurrent SI (p = 0.054) and was not associated with development of venous thromboembolism after SI (p = 0.414). In bivariate analyses, the risk of recurrent SI showed a significant association with lower platelet counts (p < 0.001) and with atrial fibrillation/flutter (p = 0.036). In a multivariable logistic regression model, no variables were identified that were associated with a higher risk of recurrent SI. SI in cancer patients is typically an isolated event with low recurrence risk. Anticoagulation use should be guided by other thromboembolic risk factors.
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http://dx.doi.org/10.1007/s11239-021-02428-0DOI Listing
March 2021

A Dose-finding Study Followed by a Phase II Randomized, Placebo-controlled Trial of Chemoradiotherapy With or Without Veliparib in Stage III Non-small-cell Lung Cancer: SWOG 1206 (8811).

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

University of California Davis, Sacramento, CA.

Background: We conducted a 2-part study to evaluate the incorporation of veliparib, a PARP inhibitor, into chemoradiotherapy (CRT) for stage III non-small-cell lung cancer.

Patients And Methods: In the phase I part, patients were treated successively at 3 dose levels of veliparib (40, 80, and 120 mg) twice daily during CRT. In the phase II part, patients were randomized to receive veliparib or placebo during thoracic radiotherapy with concurrent weekly carboplatin and paclitaxel, followed by 2 cycles of consolidation carboplatin and paclitaxel with veliparib or placebo. The study was prematurely discontinued owing to the emergence of adjuvant immunotherapy as standard of care.

Results: Of 21 patients enrolled in phase I, 2 patients developed dose-limiting toxicities (DLTs): 1 grade 3 esophagitis with dysphagia (at 40 mg) and 1 grade 3 esophagitis with dehydration (at 80 mg). No DLTs were seen at veliparib dose of 120 mg twice daily, which was selected for the phase II part that enrolled 31 eligible patients. Progression-free survival (PFS) was not different between the 2 arms (P = .20). For the veliparib and placebo arms, response rates were 56% and 69%, PFS at 1 year 47% and 46%, and overall survival at 1 year 89% and 54%, respectively.

Conclusion: Veliparib with CRT was feasible and well tolerated. Efficacy could not accurately be determined because of early study closure. Nonetheless, there is enthusiasm for the evaluation of PARP inhibitors in lung cancer as predictive biomarkers are being developed and combinations with immunotherapy are attractive.
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http://dx.doi.org/10.1016/j.cllc.2021.02.009DOI Listing
February 2021

Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response .

Cancer Discov 2021 Jul 11;11(7):1736-1753. Epub 2021 Mar 11.

Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.

In lung adenocarcinoma, oncogenic mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven -deficient lung adenocarcinoma, we found that , or inactivation strongly promoted tumor growth. Unexpectedly, inactivation of or the strongest drivers of growth in a KRAS-driven model-reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment. SIGNIFICANCE: By modeling complex genotypes , this study reveals key tumor suppressors that constrain the growth of -mutant tumors. Furthermore, we uncovered that inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1385DOI Listing
July 2021

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021.

J Natl Compr Canc Netw 2021 03 2;19(3):254-266. Epub 2021 Mar 2.

Mayo Clinic Cancer Center.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.
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http://dx.doi.org/10.6004/jnccn.2021.0013DOI Listing
March 2021

Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer.

J Clin Oncol 2021 Mar 15;39(7):723-733. Epub 2021 Jan 15.

Johns Hopkins Kimmel Cancer Center, Baltimore, MD.

Purpose: Immunotherapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials.

Methods: Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated.

Results: After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3-5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs.

Conclusion: At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.
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http://dx.doi.org/10.1200/JCO.20.01605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078445PMC
March 2021

Randomized Trial of Afatinib Plus Cetuximab Versus Afatinib Alone for First-Line Treatment of -Mutant Non-Small-Cell Lung Cancer: Final Results From SWOG S1403.

J Clin Oncol 2020 12 6;38(34):4076-4085. Epub 2020 Oct 6.

UC Davis Comprehensive Cancer Center, Sacramento, CA.

Purpose: The irreversible ErbB family tyrosine kinase inhibitor (TKI) afatinib plus the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to EGFR TKIs. We studied whether the combination of afatinib plus cetuximab compared with afatinib alone would improve progression-free survival (PFS) in patients with treatment-naive -mutant non-small-cell lung cancer (NSCLC) by preventing or delaying resistance.

Methods: Patients with -mutant NSCLC without prior treatment of advanced disease were enrolled in this phase II, multicenter trial and randomly assigned to receive afatinib 40 mg orally daily plus cetuximab 500 mg/m intravenously every 2 weeks or afatinib alone. The primary end point was PFS.

Results: Between March 25, 2015 and April 23, 2018, 174 patients were randomly assigned, and 168 (83 on afatinib + cetuximab and 85 on afatinib) were eligible. There was no improvement in PFS in patients receiving afatinib plus cetuximab compared with afatinib alone (hazard ratio [HR], 1.01; 95% CI, 0.72 to 1.43; = .94; median, 11.9 months 13.4 months). Similarly, there was no difference in response rate (67% 74%; = .38) or overall survival (HR, 0.82; 95% CI, 0.50 to 1.36; = .44). Toxicity was greater with the combination: grade ≥ 3 adverse events related to treatment occurred in 72% of patients receiving afatinib plus cetuximab compared with 40% of those receiving afatinib alone, most commonly rash and diarrhea. Dose reductions were more common in patients receiving the combination, and 30% of patients in this arm discontinued cetuximab due to toxicity. At interim analysis, there was insufficient evidence to support continued accrual, and the trial was closed.

Conclusions: The addition of cetuximab to afatinib did not improve outcomes in previously untreated -mutant NSCLC, despite recognized activity in the acquired resistance setting.
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http://dx.doi.org/10.1200/JCO.20.01149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768342PMC
December 2020

Yale Cancer Center Precision Medicine Tumor Board: new technology, new drugs, and the value of repeat testing.

Lancet Oncol 2020 03 2;21(3):343-344. Epub 2020 Mar 2.

Department of Medicine, Medical Oncology, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(20)30010-3DOI Listing
March 2020

Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial.

J Clin Oncol 2020 11 11;38(31):3592-3603. Epub 2020 Aug 11.

Royal Marsden Hospital, London, United Kingdom.

Purpose: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events).

Methods: Patients with ALK inhibitor-naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected.

Results: Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio [HR], 0.49 [95% CI, 0.35 to 0.68]; log-rank < .0001; median, 24.0 11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4 9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 [95% CI, 0.49 to 1.00]; log-rank = .049). Brigatinib daily area under the plasma concentration-time curve was not a predictor of PFS (HR, 1.005 [95% CI, 0.98 to 1.031]; = .69).

Conclusion: Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.
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http://dx.doi.org/10.1200/JCO.20.00505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605398PMC
November 2020

Clinical Activity and Safety of Atezolizumab in a Phase 1 Study of Patients With Relapsed/Refractory Small-Cell Lung Cancer.

Clin Lung Cancer 2020 09 12;21(5):455-463.e4. Epub 2020 May 12.

Department of Hematology and Oncology, HonorHealth Research Institute, Scottsdale, AZ.

Background: Programmed death-ligand 1 (PD-L1) protein is expressed in various cancers, including small-cell lung cancer (SCLC). Atezolizumab inhibits PD-L1 signaling, thus restoring tumor-specific T-cell immunity. Here, we report results from the first-in-human phase 1 PCD4989g study (NCT01375842) of atezolizumab, in a cohort of patients with relapsed/refractory SCLC.

Patients And Methods: Eligible patients with incurable or metastatic SCLC, which was advanced or recurrent since the last antitumor therapy, received atezolizumab 15 mg/kg or 1200 mg intravenously every 3 weeks for 16 cycles or until loss of clinical benefit. The primary endpoint was safety. Efficacy and biomarkers of antitumor activity were also assessed.

Results: Seventeen patients were enrolled. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 (64.7%) and 5 (29.4%) patients, respectively. The most common any-grade TRAE was fatigue (4 patients [23.5%]). Partial response to atezolizumab was achieved in 1 patient (5.9%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and 3 (17.6%) per immune-related response criteria (irRC). Durations of response were 2.8 to > 45.7 months. Median investigator-assessed progression-free survival (PFS) per RECIST v1.1 and irRC was 1.5 (95% confidence interval [CI], 1.2-2.7) and 2.9 (95% CI, 1.2-6.1) months, respectively. Median overall survival (OS) was 5.9 months (95% CI, 4.3-12.6). Patients with high (≥ median expression) T-effector gene signature and PD-L1 mRNA expression appeared to show a trend toward improved PFS (per irRC) and OS.

Conclusion: Atezolizumab was generally well tolerated and exhibited antitumor activity in a small cohort of patients with relapsed/refractory SCLC.
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http://dx.doi.org/10.1016/j.cllc.2020.05.008DOI Listing
September 2020

Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02).

Cancer Discov 2020 08 21;10(8):1158-1173. Epub 2020 May 21.

Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York.

This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension ( = 1), hyperglycemia ( = 1), metabolic acidosis ( = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8 T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1510DOI Listing
August 2020

Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer.

JCI Insight 2020 06 18;5(12). Epub 2020 Jun 18.

Department of Hematology/Oncology, Emory University, Atlanta, Georgia, USA.

BACKGROUNDPD-1 and PD-L1 have been studied interchangeably in the clinic as checkpoints to reinvigorate T cells in diverse tumor types. Data for biologic effects of checkpoint blockade in human premalignancy are limited.METHODSWe analyzed the immunologic effects of PD-L1 blockade in a clinical trial of atezolizumab in patients with asymptomatic multiple myeloma (AMM), a precursor to clinical malignancy. Genomic signatures of PD-L1 blockade in purified monocytes and T cells in vivo were also compared with those following PD-1 blockade in lung cancer patients. Effects of PD-L1 blockade on monocyte-derived DCs were analyzed to better understand its effects on myeloid antigen-presenting cells.RESULTSIn contrast to anti-PD-1 therapy, anti-PD-L1 therapy led to a distinct inflammatory signature in CD14+ monocytes and increase in myeloid-derived cytokines (e.g., IL-18) in vivo. Treatment of AMM patients with atezolizumab led to rapid activation and expansion of circulating myeloid cells, which persisted in the BM. Blockade of PD-L1 on purified monocyte-derived DCs led to rapid inflammasome activation and synergized with CD40L-driven DC maturation, leading to greater antigen-specific T cell expansion.CONCLUSIONThese data show that PD-L1 blockade leads to distinct systemic immunologic effects compared with PD-1 blockade in vivo in humans, particularly manifest as rapid myeloid activation. These findings also suggest an additional role for PD-L1 as a checkpoint for regulating inflammatory phenotype of myeloid cells and antigen presentation in DCs, which may be harnessed to improve PD-L1-based combination therapies.TRIAL REGISTRATIONNCT02784483.FUNDINGThis work is supported, in part, by funds from NIH/NCI (NCI CA197603, CA238471, and CA208328).
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http://dx.doi.org/10.1172/jci.insight.129353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406262PMC
June 2020

Biomarkers Associated with Beneficial PD-1 Checkpoint Blockade in Non-Small Cell Lung Cancer (NSCLC) Identified Using High-Plex Digital Spatial Profiling.

Clin Cancer Res 2020 08 6;26(16):4360-4368. Epub 2020 Apr 6.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Purpose: Only a minority of patients with advanced non-small cell lung cancer (NSCLC) truly benefits from single-agent PD-1 checkpoint blockade, and more robust predictive biomarkers are needed.

Experimental Design: We assessed tumor samples from 67 immunotherapy-treated NSCLC cases represented in a tissue microarray, 53 of whom had pretreatment samples and received monotherapy. Using GeoMx Digital Spatial Profiling System (NanoString Technologies), we quantified 39 immune parameters simultaneously in four tissue compartments defined by fluorescence colocalization [tumor (panCK), leucocytes (CD45), macrophages (CD68), and nonimmune stroma].

Results: A total of 156 protein variables were generated per case. In the univariate unadjusted analysis, we found 18 markers associated with outcome in spatial context, five of which remained significant after multiplicity adjustment. In the multivariate analysis, high levels of CD56 and CD4 measured in the CD45 compartment were the only markers that were predictive for all clinical outcomes, including progression-free survival (PFS, HR: 0.24, = 0.006; and HR: 0.31, = 0.011, respectively), and overall survival (OS, HR: 0.26, = 0.014; and HR: 0.23, = 0.007, respectively). Then, using an orthogonal method based on multiplex immunofluorescence and cell counting (inForm), we validated that high CD56 immune cell counts in the stroma were associated with PFS and OS in the same cohort.

Conclusions: This pilot scale discovery study shows the potential of the digital spatial profiling technology in the identification of spatially informed biomarkers of response to PD-1 checkpoint blockade in NSCLC. We identified a number of relevant candidate immune predictors in spatial context that deserve validation in larger independent cohorts.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442721PMC
August 2020

Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial.

Lancet Oncol 2020 05 3;21(5):655-663. Epub 2020 Apr 3.

Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT, USA.

Background: We did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort.

Methods: This was an open-label, phase 2 study of patients from the Yale Cancer Center (CT, USA). Eligible patients were at least 18 years of age with stage IV NSCLC with at least one brain metastasis 5-20 mm in size, not previously treated or progressing after previous radiotherapy, no neurological symptoms or corticosteroid requirement, and Eastern Cooperative Oncology Group performance status less than two. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was used to evaluate CNS disease; systemic disease was not required for participation. Patients were treated with pembrolizumab 10 mg/kg intravenously every 2 weeks. Patients were in two cohorts: cohort 1 was for those with PD-L1 expression of at least 1% and cohort 2 was patients with PD-L1 less than 1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response (partial response or complete response, according to mRECIST). All treated patients were analysed for response and safety endpoints. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT02085070.

Findings: Between March 31, 2014, and May 21, 2018, 42 patients were treated. Median follow-up was 8·3 months (IQR 4·5-26·2). 11 (29·7% [95% CI 15·9-47·0]) of 37 patients in cohort 1 had a brain metastasis response. There were no responses in cohort 2. Grade 3-4 adverse events related to treatment included two patients with pneumonitis, and one each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycaemia, and hypokalaemia. Treatment-related serious adverse events occurred in six (14%) of 42 patients and were pneumonitis (n=2), acute kidney injury, colitis, hypokalaemia, and adrenal insufficiency (n=1 each). There were no treatment-related deaths.

Interpretation: Pembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression at least 1% and is safe in selected patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted.

Funding: Merck and the Yale Cancer Center.
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http://dx.doi.org/10.1016/S1470-2045(20)30111-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380514PMC
May 2020

Oligometastatic Disease and Local Therapies: A Medical Oncology Perspective.

Cancer J 2020 Mar/Apr;26(2):144-148

From the Yale Cancer Center, Yale University, New Haven, CT.

Numerous studies in a variety of solid tumor malignancies have demonstrated prolonged progression-free and overall survival with the addition of definitive local therapies to systemic therapies in patients with a limited number of metastases. A subset of patients with oligometastases (1-5 metastases) may experience long-term disease remission or cure after local therapies such as surgery or stereotactic body radiation therapy to metastatic sites. This article reviews the literature in oligometastatic disease and considers a theoretical rationale for a curative approach in a subset of oligometastatic solid tumor patients. In oligometastatic colorectal cancer patients with liver-only metastases and in non-small cell lung cancer patients with disease control after primary therapy and with limited nodal involvement, aggressive local therapies should be considered. Clinical trials and further biomarker validation across disease types are necessary to clarify which subsets of patients may define a theorized "oligometastatic state" and therefore benefit from aggressive local therapies.
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http://dx.doi.org/10.1097/PPO.0000000000000439DOI Listing
April 2021

Immune Checkpoint Inhibitors in Thoracic Malignancies: Review of the Existing Evidence by an IASLC Expert Panel and Recommendations.

J Thorac Oncol 2020 06 14;15(6):914-947. Epub 2020 Mar 14.

Department of Oncology, University of Torino, AOU S. Luigi Gonzaga, Orbassano, Italy. Electronic address:

In the past 10 years, a deeper understanding of the immune landscape of cancers, including immune evasion processes, has allowed the development of a new class of agents. The reactivation of host antitumor immune response offers the potential for long-term survival benefit in a portion of patients with thoracic malignancies. The advent of programmed cell death protein 1/programmed death ligand-1 immune checkpoint inhibitors (ICIs), both as single agents and in combination with chemotherapy, and more recently, the combination of ICI, anti-programmed cell death protein 1, and anticytotoxic T-lymphocyte antigen 4 antibody, have led to breakthrough therapeutic advances for patients with advanced NSCLC, and to a lesser extent, patients with SCLC. Encouraging activity has recently emerged in pretreated patients with thymic carcinoma (TC). Conversely, in malignant pleural mesothelioma, pivotal positive signs of activity have not been fully confirmed in randomized trials. The additive effects of chemoradiation and immunotherapy suggested intriguing potential for therapeutic synergy with combination strategies. This has led to the introduction of ICI consolidation therapy in stage III NSCLC, creating a platform for future therapeutic developments in earlier-stage disease. Despite the definitive clinical benefit observed with ICI, primary and acquired resistance represent well-known biological phenomena, which may affect the therapeutic efficacy of these agents. The development of innovative strategies to overcome ICI resistance, standardization of new patterns of ICI progression, identification of predictive biomarkers of response, optimal treatment duration, and characterization of ICI efficacy in special populations, represent crucial issues to be adequately addressed, with the aim of improving the therapeutic benefit of ICI in patients with thoracic malignancies. In this article, an international panel of experts in the field of thoracic malignancies discussed these topics, evaluating currently available scientific evidence, with the final aim of providing clinical recommendations, which may guide oncologists in their current practice and elucidate future treatment strategies and research priorities.
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http://dx.doi.org/10.1016/j.jtho.2020.03.006DOI Listing
June 2020

Phase 1 study of epacadostat in combination with atezolizumab for patients with previously treated advanced nonsmall cell lung cancer.

Int J Cancer 2020 10 20;147(7):1963-1969. Epub 2020 Mar 20.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

Epacadostat is a potent and highly selective inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1). Here we report results from the open-label, dose-escalation, Phase 1b ECHO-110 study evaluating epacadostat plus atezolizumab in patients with previously treated Stage IIIB/IV nonsmall cell lung cancer (NSCLC). Eligible patients had received ≥1 prior line of platinum-based chemotherapy (≥2 cycles) and no prior checkpoint/IDO inhibitors treatment. Oral epacadostat (25, 50, 75, 100, 200 or 300 mg) was administered twice daily (BID) with intravenous atezolizumab 1,200 mg every 3 weeks (Q3W). Primary endpoints were safety, tolerability and dose-limiting toxicities (DLTs). Twenty-nine patients received ≥1 dose of treatment. The maximum tolerated dose of epacadostat was not reached. Two patients had DLTs: one patient with Grade 3 dehydration and hypotension (epacadostat 200 mg BID); one patient with Grade 3 hyponatremia and Grade 4 autoimmune encephalitis (epacadostat 300 mg BID). Twenty-three patients (79%) had treatment-related adverse events (AEs); seven patients (24%) experienced Grade 3/4 events; five patients (17%) discontinued treatment due to treatment-related AEs. No fatal treatment-related AEs occurred. One patient achieved a partial response (objective response rate, 3%), which was maintained for 8.3 months; eight patients had stable disease. Baseline tumoral programmed cell death ligand 1 (PD-L1) and IDO expression were low among patients with evaluable samples (1 of 23 expressed PD-L1; 5 of 17 expressed IDO). Epacadostat pharmacokinetics was comparable to historical controls. Epacadostat, at doses up to 300 mg BID, combined with atezolizumab 1,200 mg Q3W was well tolerated in patients with previously treated NSCLC, although clinical activity was limited.
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http://dx.doi.org/10.1002/ijc.32951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496129PMC
October 2020

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

JAMA Oncol 2020 06;6(6):848-855

Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University.

Importance: Consolidative programmed death ligand-1 (PD-L) inhibition after chemoradiotherapy improves overall survival and progression-free survival (PFS) for stage III non-small cell lung cancer (NSCLC) and requires safety evaluation for incorporation of programmed cell death 1 (PD-1) inhibition at the onset of chemoradiotherapy.

Objective: To determine the safety and tolerability of PD-1 inhibition concurrently with definitive chemoradiotherapy for NSCLC.

Design, Setting, And Participants: This phase 1 prospective multicenter nonrandomized controlled trial using a 3 plus 3 design was performed from August 30, 2016, to October 24, 2018, with a median follow-up of 16.0 (95% CI, 12.0-22.6) months and data locked on July 25, 2019. Twenty-one participants had locally advanced, unresectable, stage III NSCLC as determined by multidisciplinary review, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function. Data were analyzed from October 17, 2016, to July 19, 2019.

Interventions: Pembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Dose cohorts evaluated included full-dose pembrolizumab (200 mg intravenously every 3 weeks) 2 to 6 weeks after chemoradiotherapy (cohort 1); reduced-dose pembrolizumab (100 mg intravenously every 3 weeks) starting day 29 of chemoradiotherapy (cohort 2); full-dose pembrolizumab starting day 29 of chemoradiotherapy (cohort 3); reduced-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 4); and full-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 5). A safety expansion cohort of 6 patients was planned based on the maximum tolerated dose of pembrolizumab. Dose-limiting toxic effects were defined as pneumonitis of at least grade 4 within cycle 1 of pembrolizumab treatment.

Main Outcomes And Measures: Safety and tolerability of PD-1 inhibition with chemoradiotherapy for NSCLC. Secondary outcomes included PFS and pneumonitis rates.

Results: Among the 21 patients included in the analysis (11 female [52%]; median age, 69.5 [range, 53.0-85.0] years), no dose-limiting toxic effects in any cohort were observed. One case of grade 5 pneumonitis occurred in the safety expansion cohort with the cohort 5 regimen. Immune-related adverse events of at least grade 3 occurred in 4 patients (18%). Median PFS for patients who received at least 1 dose of pembrolizumab (n = 21) was 18.7 (95% CI, 11.8-29.4) months, and 6- and 12-month PFS were 81.0% (95% CI, 64.1%-97.7%) and 69.7% (95% CI, 49.3%-90.2%), respectively. Median PFS for patients who received at least 2 doses of pembrolizumab (n = 19) was 21.0 (95% CI, 15.3 to infinity) months.

Conclusions And Relevance: These findings suggest that combined treatment with PD-1 inhibitors and chemoradiotherapy for stage III NSCLC is tolerable, with promising PFS of 69.7% at 12 months, and requires further study.

Trial Registration: ClinicalTrials.gov Identifier: NCT02621398.
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http://dx.doi.org/10.1001/jamaoncol.2019.6731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042914PMC
June 2020

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 1.2020.

J Natl Compr Canc Netw 2019 12;17(12):1464-1472

1The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as "preferred interventions," whereas others are categorized as either "other recommended interventions" or "useful under certain circumstances."
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http://dx.doi.org/10.6004/jnccn.2019.0059DOI Listing
December 2019

Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial.

J Thorac Oncol 2020 03 19;15(3):404-415. Epub 2019 Nov 19.

University of Colorado Cancer Center, Aurora, Colorado.

Introduction: We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase-positive NSCLC.

Methods: Patients were randomized 1:1 to take either oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (arm B), stratified by central nervous system (CNS) metastases and best response to crizotinib. The primary end point was investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included independent review committee (IRC)-assessed progression-free survival (PFS), intracranial PFS (iPFS), and overall survival (OS). Exploratory analyses included CNS versus ex-CNS target lesion response and correlation of depth of response with PFS and OS.

Results: Among 222 randomized patients (112 and 110 in arms A and B, respectively), 59 (27%) remained on brigatinib at analysis (median follow-up: 19.6 versus 24.3 months). At baseline, 71% and 67% had brain lesions among A and B arms, respectively. Investigator-assessed confirmed objective response rate was 46% versus 56%. Median IRC-assessed PFS was 9.2 months (95% confidence interval: 7.4-12.8) versus 16.7 months (11.6-21.4). Median OS was 29.5 months (18.2-not reached) versus 34.1 months (27.7-not reached). IRC-confirmed intracranial objective response rate in patients with measurable baseline brain lesions was 50% (13 of 26) versus 67% (12 of 18); median duration of intracranial response was 9.4 versus 16.6 months. IRC-assessed iPFS was 12.8 versus 18.4 months. Across arms, median IRC-assessed PFS was 1.9, 5.5, 11.1, 16.7, and 15.6 months for patients with no, 1%-25%, 26%-50%, 51%-75%, and 76%-100% target lesion shrinkage, respectively. No new safety findings were observed with longer follow-up.

Conclusions: Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials.
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http://dx.doi.org/10.1016/j.jtho.2019.11.004DOI Listing
March 2020

Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy.

Clin Cancer Res 2020 02 15;26(4):970-977. Epub 2019 Oct 15.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Purpose: Programmed death ligand 1 (PD-L1) is expressed in tumor cells and immune cells, and both have been associated with response to anti-PD-1 axis immunotherapy. Here, we examine the expression of PD-L1 to determine which cell type carries the predictive value of the test.

Experimental Design: We measured the expression of PD-L1 in multiple immune cells with two platforms and confocal microscopy on three retrospective Yale NSCLC cohorts (425 nonimmunotherapy-treated cases and 62 pembrolizumab/nivolumab/atezolizumab-treated cases). The PD-L1 level was selectively measured in different immune cell subsets using two multiplexed quantitative immunofluorescence panels, including CD56 for natural killer cells, CD68 for macrophages, and CD8 for cytotoxic T cells.

Results: PD-L1 was significantly higher in macrophages in both tumor and stromal compartment compared with other immune cells. Elevated PD-L1 in macrophages was correlated with high PD-L1 level in tumor as well as CD8 and CD68 level ( < 0.0001). High PD-L1 expression in macrophages was correlated with better overall survival (OS; = 0.036 by cell count/ = 0.019 by molecular colocalization), while high PD-L1 expression in tumor cells was not.

Conclusions: In nearly 500 non-small cell lung cancer (NSCLC) cases, the predominant immune cell type that expresses PD-L1 is CD68 macrophages. The level of PD-L1 in macrophages is significantly associated with the level of PD-L1 in tumor cells and infiltration by CD8 T cells, suggesting a connection between high PD-L1 and "hot" tumors. In anti-PD-1 axis therapy-treated patients, high levels of PD-L1 expression in macrophages are associated with longer OS and may be responsible for the predictive effect of the marker.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024671PMC
February 2020

Quantitative Assessment of CMTM6 in the Tumor Microenvironment and Association with Response to PD-1 Pathway Blockade in Advanced-Stage Non-Small Cell Lung Cancer.

J Thorac Oncol 2019 12 9;14(12):2084-2096. Epub 2019 Oct 9.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine (Oncology), Yale University School of Medicine, New Haven, Connecticut. Electronic address:

Introduction: CKLF like MARVEL transmembrane domain containing 6 (CMTM6) has been described as a programmed death ligand 1 (PD-L1) regulator at the protein level by modulating stability through ubiquitination. In this study, we describe the patterns of CMTM6 expression and assess its association with response to programmed cell death 1 pathway blockade in NSCLC.

Methods: We used multiplexed quantitative immunofluorescence to determine the expression of CMTM6 and PD-L1 in 438 NSCLCs represented in tissue microarrays, including in two independent retrospective cohorts of immunotherapy-treated (n = 69) and non-immunotherapy-treated (n = 258) patients and a third collection of EGFR- and KRAS-genotyped tumors (n = 111).

Results: Tumor and stromal CMTM6 expression was detected in approximately 70% of NSCLCs. CMTM6 expression was not associated with clinical features or EGFR/KRAS mutational status and showed a modest correlation with T-cell infiltration (R < 0.40). We found a significant correlation between CMTM6 and PD-L1, which was higher in the stroma (R = 0.51) than in tumor cells (R = 0.35). In our retrospective NSCLC cohort, neither CMTM6 nor PD-L1 expression alone significantly predicted immunotherapy outcomes. However, high CMTM6 and PD-L1 coexpression in the stromal and CD68 compartments (adjusted hazard ratio = 0.38, p = 0.03), but not in tumor cells (p = 0.15), was significantly associated with longer overall survival in treated patients but was not observed in the absence of immunotherapy.

Conclusion: This study supports the mechanistic role for CMTM6 in stabilization of PD-L1 in patient tumors and suggests that high coexpression of CMTM6 and PD-L1, particularly in stromal immune cells (macrophages), might identify the greatest benefit from programmed cell death 1 axis blockade in NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2019.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951804PMC
December 2019

Comparison of Survival Rates After a Combination of Local Treatment and Systemic Therapy vs Systemic Therapy Alone for Treatment of Stage IV Non-Small Cell Lung Cancer.

JAMA Netw Open 2019 08 2;2(8):e199702. Epub 2019 Aug 2.

Section of Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut.

Importance: As many as 55% of patients with non-small cell lung cancer (NSCLC) present with stage IV disease at diagnosis. Although systemic therapy is the cornerstone for treatment of these patients, growing evidence suggests that local treatment of the primary tumor site may improve survival.

Objective: To assess whether addition of local treatment for primary tumor site in stage IV NSCLC provides a survival benefit over systemic therapy alone.

Design, Setting, And Participants: In this comparative effectiveness research study, the National Cancer Database (NCDB; 2018 version) was retrospectively queried from January 1, 2010, through December 31, 2015, for patients with a histopathologic diagnosis of stage IV NSCLC. Exclusion criteria were being younger than 18 years and missing information on tumor characteristics and follow-up data. Data were analyzed from November 1, 2018, through January 1, 2019.

Exposures: Treatment groups were stratified as (1) surgical resection plus systemic therapy; (2) external beam radiotherapy (EBRT) or thermal ablation (TA; including cryosurgery and radiofrequency ablation) plus systemic therapy; and (3) systemic therapy alone.

Main Outcomes And Measures: Overall survival was compared between treatment groups using multivariable Cox proportional hazards regression models and after propensity score matching. Subgroup analyses were planned a priori according to patient and tumor characteristics.

Results: A total of 34 887 patients met inclusion criteria (19 002 male [54.5%]; median age, 68 years [interquartile range, 60-75 years]), among whom 835 underwent surgical resection plus systemic therapy; 9539, EBRT/TA plus systemic therapy; and 24 513, systemic therapy alone. Demographic and cancer-specific factors were associated with treatment allocation with a higher likelihood of surgical resection for oligometastatic NSCLC. After multivariable adjustment, surgical resection was associated with superior overall survival compared with EBRT/TA or systemic therapy alone (hazard ratio [HR] for EBRT/TA, 0.62; 95% CI, 0.57-0.67; P < .001; HR for systemic therapy alone, 0.59; 95% CI, 0.55-0.64; P < .001). Treatment with EBRT/TA demonstrated superior overall survival compared with systemic therapy alone (HR, 0.95; 95% CI, 0.93-0.98; P = .002). Interaction analyses identified heterogeneous associations with treatment; the EBRT/TA survival benefit was especially pronounced in stage IV squamous cell carcinoma with limited T and N category disease and oligometastases (HR, 0.68; 95% CI, 0.57-0.80; P < .001), with overall survival rates of 60.4% vs 45.4% at 1 year, 32.6% vs 19.2% at 2 years, and 20.2% vs 10.6% at 3 years for combination therapy vs systemic therapy alone.

Conclusions And Relevance: In stage IV NSCLC, surgical resection or EBRT/TA of the primary tumor site may provide survival benefits in addition to systemic therapy alone in selected patients. Specifically, EBRT/TA may be considered as a treatment option in select patients who are ineligible for surgical resection.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.9702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707019PMC
August 2019

Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis.

Lancet Oncol 2019 10 14;20(10):1395-1408. Epub 2019 Aug 14.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.

Background: Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival.

Methods: We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab.

Findings: Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11-17) for all patients (n=664), 19% (15-24) for those with at least 1% PD-L1 expression, and 11% (7-16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11-18) in patients treated with nivolumab, compared with 5% (3-7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0·18 (95% 0·12-0·27) for nivolumab and 0·43 (0·29-0·65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52 (0·37-0·71) for nivolumab and 0·80 (0·61-1·04) for docetaxel. Long-term data did not show any new safety signals.

Interpretation: Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage.

Funding: Bristol-Myers Squibb.
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http://dx.doi.org/10.1016/S1470-2045(19)30407-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193685PMC
October 2019

Five-Year Survival and Correlates Among Patients With Advanced Melanoma, Renal Cell Carcinoma, or Non-Small Cell Lung Cancer Treated With Nivolumab.

JAMA Oncol 2019 Oct;5(10):1411-1420

Department of Internal Medicine (Section of Medical Oncology), Yale Cancer Center, New Haven, Connecticut.

Importance: Nivolumab, a monoclonal antibody that inhibits programmed cell death 1, is approved by the US Food and Drug Administration for treating advanced melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and other malignancies. Data on long-term survival among patients receiving nivolumab are limited.

Objectives: To analyze long-term overall survival (OS) among patients receiving nivolumab and identify clinical and laboratory measures associated with tumor regression and OS.

Design, Setting, And Participants: This was a secondary analysis of the phase 1 CA209-003 trial (with expansion cohorts), which was conducted at 13 US medical centers and included 270 patients with advanced melanoma, RCC, or NSCLC who received nivolumab and were enrolled between October 30, 2008, and December 28, 2011. The analyses were either specified in the original protocol or included in subsequent protocol amendments that were implemented between 2008 and 2012. Statistical analysis was performed from October 30, 2008, to November 11, 2016.

Intervention: In the CA209-003 trial, patients received nivolumab (0.1-10.0 mg/kg) every 2 weeks in 8-week cycles for up to 96 weeks, unless they developed progressive disease, achieved a complete response, experienced unacceptable toxic effects, or withdrew consent.

Main Outcomes And Measures: Safety and activity of nivolumab; OS was a post hoc end point with a minimum follow-up of 58.3 months.

Results: Of 270 patients included in this analysis, 107 (39.6%) had melanoma (72 [67.3%] male; median age, 61 [range, 29-85] years), 34 (12.6%) had RCC (26 [76.5%] male; median age, 58 [range, 35-74] years), and 129 (47.8%) had NSCLC (79 [61.2%] male; median age, 65 [range, 38-85] years). Overall survival curves showed estimated 5-year rates of 34.2% among patients with melanoma, 27.7% among patients with RCC, and 15.6% among patients with NSCLC. In a multivariable analysis, the presence of liver (odds ratio [OR], 0.31; 95% CI, 0.12-0.83; P = .02) or bone metastases (OR, 0.31; 95% CI, 0.10-0.93; P = .04) was independently associated with reduced likelihood of survival at 5 years, whereas an Eastern Cooperative Oncology Group performance status of 0 (OR, 2.74; 95% CI, 1.43-5.27; P = .003) was independently associated with an increased likelihood of 5-year survival. Overall survival was significantly longer among patients with treatment-related AEs of any grade (median, 19.8 months; 95% CI, 13.8-26.9 months) or grade 3 or more (median, 20.3 months; 95% CI, 12.5-44.9 months) compared with those without treatment-related AEs (median, 5.8 months; 95% CI, 4.6-7.8 months) (P < .001 for both comparisons based on hazard ratios).

Conclusions And Relevance: Nivolumab treatment was associated with long-term survival in a subset of heavily pretreated patients with advanced melanoma, RCC, or NSCLC. Characterizing factors associated with long-term survival may inform treatment approaches and strategies for future clinical trial development.

Trial Registration: ClinicalTrials.gov identifier: NCT00730639.
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http://dx.doi.org/10.1001/jamaoncol.2019.2187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659167PMC
October 2019

The EGFR Exon 19 Mutant L747-A750>P Exhibits Distinct Sensitivity to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma.

Clin Cancer Res 2019 11 10;25(21):6382-6391. Epub 2019 Jun 10.

Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.

Purpose: exon 19 deletion (Ex19Del) mutations account for approximately 60% of lung cancer-associated mutations and include a heterogeneous group of mutations. Although they are associated with benefit from tyrosine kinase inhibitors (TKI), the relative inhibitor sensitivity of individual Ex19Del mutations is unknown. We studied the TKI sensitivity and structural features of common Ex19Del mutations and the consequences for patient outcomes on TKI treatment.

Results: We found that the L747-A750>P mutation, which represents about 4% of all Ex19Del mutations, displays unique inhibitor selectivity. L747-A750>P differs from other Ex19Del mutations in not being suppressed completely by erlotinib or osimertinib, yet is completely inhibited by low doses of afatinib. The HCC4006 cell line (with the L747-A750>P mutation) exhibited increased sensitivity to afatinib over erlotinib and osimertinib, and computational modeling suggests explanations for this sensitivity pattern. Clinically, patients with EGFR L747-A750>P mutant tumors showed inferior outcomes when treated with erlotinib than patients with E746-A750 mutant tumors.

Conclusions: These results highlight important differences between specific Ex19Del mutations that may be relevant for optimizing TKI choice for patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825535PMC
November 2019

Incidence of pancreatitis with the use of immune checkpoint inhibitors (ICI) in advanced cancers: A systematic review and meta-analysis.

Pancreatology 2019 Jun 2;19(4):587-594. Epub 2019 May 2.

Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

Background: Systemic immune side effects including pancreatitis have been reported with the use of Immune Checkpoint Inhibitors (ICI) (CTLA-4, PD-1 and PDL-1). However, the true incidence, risk, causes (tumor or drug specific) of pancreatitis and relation to other immune side effects, especially diabetes mellitus (DM) are unknown.

Methods: We performed a systematic review and meta-analysis of all clinical trials using ICI for the incidence of any grade lipase elevation, pancreatitis or DM.

Results: The incidence of asymptomatic lipase elevation after ICI use is 2.7% (211/7702) and grade 2 pancreatitis is 1.9% (150/7702). No pancreatitis related mortality has been reported in these clinical trials. Patients treated with CTLA-4 inhibitors have increased incidence of pancreatitis when compared to patients treated with PD1 inhibitors 3.98% (95% CI: 2.92 to 5.05) vs 0.94% (95% CI: 0.48 to 1.40); P value < 0.05. Patients treated with ICI for melanoma have increased incidence of pancreatitis when compared to non-melanoma cancers. We also noted an additive increase in incidence of pancreatitis with combination of CTLA4 and PD-1 inhibitors (10.60; 95% CI: 7.89 to 13.32) compared with either CTLA-4 or PD-1 inhibitors alone.

Conclusions: Our study provides precise data for the incidence of pancreatitis among patients using ICI based on tumor types and ICI regimens. ICI use for solid tumors is associated with increased incidence of all grades of lipase elevation and pancreatitis, especially for CTLA-4 agents and ICI combination. Although it does not appear to be associated with mortality, ICI related pancreatitis should be recognized early for appropriate treatment and to potentially reduce long term complications.
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http://dx.doi.org/10.1016/j.pan.2019.04.015DOI Listing
June 2019

Expression Analysis and Significance of PD-1, LAG-3, and TIM-3 in Human Non-Small Cell Lung Cancer Using Spatially Resolved and Multiparametric Single-Cell Analysis.

Clin Cancer Res 2019 08 3;25(15):4663-4673. Epub 2019 May 3.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Purpose: To determine the tumor tissue/cell distribution, functional associations, and clinical significance of PD-1, LAG-3, and TIM-3 protein expression in human non-small cell lung cancer (NSCLC).

Experimental Design: Using multiplexed quantitative immunofluorescence, we performed localized measurements of CD3, PD-1, LAG-3, and TIM-3 protein in >800 clinically annotated NSCLCs from three independent cohorts represented in tissue microarrays. Associations between the marker's expression and major genomic alterations were studied in The Cancer Genome Atlas NSCLC dataset. Using mass cytometry (CyTOF) analysis of leukocytes collected from 20 resected NSCLCs, we determined the levels, coexpression, and functional profile of PD-1, LAG-3, and TIM-3 expressing immune cells. Finally, we measured the markers in baseline samples from 90 patients with advanced NSCLC treated with PD-1 axis blockers and known response to treatment.

Results: PD-1, LAG-3, and TIM-3 were detected in tumor-infiltrating lymphocytes (TIL) from 55%, 41.5%, and 25.3% of NSCLC cases, respectively. These markers showed a prominent association with each other and limited association with major clinicopathologic variables and survival in patients not receiving immunotherapy. Expression of the markers was lower in EGFR-mutated adenocarcinomas and displayed limited association with tumor mutational burden. In single-cell CyTOF analysis, PD-1 and LAG-3 were predominantly localized on T-cell subsets/NKT cells, whereas TIM-3 expression was higher in NK cells and macrophages. Coexpression of PD-1, LAG-3, and TIM-3 was associated with prominent T-cell activation (CD69/CD137), effector function (Granzyme-B), and proliferation (Ki-67), but also with elevated levels of proapoptotic markers (FAS/BIM). LAG-3 and TIM-3 were present in TIL subsets lacking PD-1 expression and showed a distinct functional profile. In baseline samples from 90 patients with advanced NSCLC treated with PD-1 axis blockers, elevated LAG-3 was significantly associated with shorter progression-free survival.

Conclusions: PD-1, LAG-3, and TIM-3 have distinct tissue/cell distribution, functional implications, and genomic correlates in human NSCLC. Expression of these immune inhibitory receptors in TILs is associated with prominent activation, but also with a proapoptotic T-cell phenotype. Elevated LAG-3 expression is associated with insensitivity to PD-1 axis blockade, suggesting independence of these immune evasion pathways.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444693PMC
August 2019
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