Publications by authors named "Biagio Ricciuti"

82 Publications

SMARCA4 and other SWI/SNF family genomic alterations in non-small cell lung cancer: Clinicopathological characteristics and outcomes to immune checkpoint inhibition.

J Thorac Oncol 2021 Apr 9. Epub 2021 Apr 9.

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA. Electronic address:

Introduction: The SWI/SNF (SWitch/Sucrose Non-Fermentable) chromatin remodeling complex acts as a regulatory component of transcription, and inactivating mutations within the complex are implicated in genomic instability, higher tumor mutational burden (TMB), and an aggressive cancer phenotype. Whether SMARCA4 and other SWI/SNF alterations are independent prognostic factors or associated with clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC remains unclear.

Methods: We collected clinicopathologic and genomic data from patients with NSCLC that underwent targeted next-generation sequencing (NGS) at the Dana-Farber Cancer Institute. Tumors were characterized based on the presence or absence of mutations across a set of 6 SWI/SNF genes (ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1).

Results: Of 2689 patients with NSCLC, 20.6% (N=555) had SWI/SNF genomic alterations. Compared to SWI/SNF wild-type (wt) NSCLC, patients with SWI/SNF mutant NSCLCs had a lower prevalence of concurrent targetable driver mutations (33.2% vs 22.2%; P<0.001), a higher TMB (median 8.5 vs 12.2 mutations/megabase; P<0.001), a shorter median overall survival (mOS) from the time of advanced disease diagnosis (25.0 vs 19.3 months; P=0.01); the detrimental effect in OS appeared to be largely driven by SMARCA4 mutations (mOS: 25.0 months for SMARCA4 wt vs 15.6 months for SMARCA4 mutant; P<0.001). Among 532 patients who received ICIs, 25.5% (N=136) harbored SWI/SNF mutations. From the start of immunotherapy, there was no difference in objective response rate (ORR 19.9% vs 25.0%; P=0.2), median progression-free survival (mPFS 3.0 vs 3.0 months; HR: 0.96 [95% CI: 0.77-1.18]; P=0.7), or mOS (13.1 vs 9.5 months; HR: 0.81 [95% CI: 0.64-1.02]; P=0.07) in SWI/SNF wt vs SWI/SNF mutant NSCLC, respectively. However, among KRAS-mutant NSCLCs treated with ICIs (N=176), a concurrent SWI/SNF mutation (N=39) conferred a numerically lower ORR (21.9% vs 12.8%; P=0.2), a significantly shorter mPFS (4.1 vs 1.8 months; HR: 0.57 [95%CI: 0.38-0.84]; P=0.005), and a significantly shorter mOS (15.5 vs 8.2 months; HR: 0.56 [95%CI: 0.36-0.86]; P=0.008). The deleterious effect on immunotherapy outcomes in KRAS-mutant NSCLC was most pronounced in the SMARCA4-mutant subset (N=17), with a lower ORR (22% vs 0%, P=0.03) a significantly shorter mPFS (4.1 vs 1.4 months; HR: 0.25 [95%CI: 0.14-0.42]; P<0.001), and a significantly shorter mOS (15.1 vs 3.0 months; HR: 0.29 [95%CI: 0.17-0.50]; P<0.001) compared to SMARCA4-wt KRAS-mutant NSCLCs.

Conclusions: Although there were no significant associations between SWI/SNF mutation status and immunotherapy efficacy in the overall NSCLC cohort, the presence of a SMARCA4 alteration may confer a worse outcome to immunotherapy among KRAS-mutant NSCLCs.
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http://dx.doi.org/10.1016/j.jtho.2021.03.024DOI Listing
April 2021

Systemic effect of radiotherapy before or after nivolumab in lung cancer: an observational, retrospective, multicenter study.

Tumori 2021 Apr 4:3008916211004733. Epub 2021 Apr 4.

Department of Oncology, San Camillo de Lellis Hospital, Rieti, Italy.

Background: The combination of radiotherapy (RT) and programmed death 1 inhibitors seems to increase antitumor immune responses.

Objective: To assess the outcome and the role of the best combination sequence, i.e. immunotherapy given before, during, and/or after RT, in patients with non-small cell lung cancer (NSCLC).

Methods: We conducted an observational, retrospective analysis of 95 consecutive patients with advanced NSCLC who received any radiotherapy treatment and nivolumab, as clinically indicated. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan-Meier method. Cox model was used to obtain hazard ratio (HR) and associated 95% CI with statistical inference by log-rank statistic.

Results: Median OS was 11.9 months (95% CI, 6.6-17.2). Patients who received radiotherapy during an immune checkpoint inhibitor treatment started more than 60 days before showed a better outcome than patients who started immunotherapy over 60 days after RT ending (HR, 2.90 [1.37-6.12], = 0.005; median OS, 22.4 months vs 8.6 months, = 0.005). Median progression-free survival was 6.3 months (95% CI, 4.6-8.0).

Conclusions: This study shows that combining irradiation with nivolumab for the treatment of advanced NSCLC leads to improved OS. The optimal time window for the combination of RT and immunotherapy seems to play a critical role for therapeutic antitumor response derived by abscopal effect.
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http://dx.doi.org/10.1177/03008916211004733DOI Listing
April 2021

Early plasma circulating tumor DNA (ctDNA) changes predict response to first-line pembrolizumab-based therapy in non-small cell lung cancer (NSCLC).

J Immunother Cancer 2021 Mar;9(3)

Medical Oncology, Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA

Background: Currently available biomarkers are imperfect in their ability to predict responses to the multiple first-line treatment options available for patients with advanced non-small cell lung cancer (NSCLC). Having an early pharmacodynamic marker of treatment resistance may help redirect patients onto more effective alternative therapies. We sought to determine if changes in circulating tumor DNA (ctDNA) levels after initiation of first-line pembrolizumab±chemotherapy in NSCLC would enable early prediction of response prior to radiological assessment.

Methods: Plasma collected from patients with advanced NSCLC prior to and serially after starting first-line pembrolizumab±platinum doublet chemotherapy was analyzed by next-generation sequencing using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes. Early change in ctDNA allele fraction (AF) was correlated with radiographic responses and long-term clinical outcomes.

Results: Among 62 patients who received first-line pembrolizumab±platinum/pemetrexed and underwent ctDNA assessment, 45 had detectable ctDNA alterations at baseline. The median change in AF at the first follow-up (at a median of 21 days after treatment initiation) was -90.1% (range -100% to +65%) among patients who subsequently had a radiologic response (n=18), -19.9% (range: -100% to +1884%) among stable disease cases (n=15), and +28.8% (range: -100% to +410%) among progressive disease cases (n=12); p=0.003. In addition, there was a significant correlation between the percent change in ctDNA at the first follow-up and the percent change in tumor target lesions from baseline (R=0.66, p<0.001). AF decrease between the pretreatment and first on-treatment blood draw was associated with significantly higher response rate (60.7% vs 5.8%, p=0.0003), and significantly longer median progression-free survival (8.3 vs 3.4 months, HR: 0.29 (95% CI: 0.14 to 0.60), p=0.0007) and median overall survival (26.2 vs 13.2 months, HR: 0.34 (95% CI: 0.15 to 0.75), p=0.008) compared with cases with an AF increase.

Conclusion: In patients with advanced NSCLC, rapid decreases in ctDNA prior to radiological assessment correlated with clinical benefit. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.
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http://dx.doi.org/10.1136/jitc-2020-001504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996662PMC
March 2021

Exclusion of patients living with HIV from cancer immune checkpoint inhibitor trials.

Sci Rep 2021 Mar 23;11(1):6637. Epub 2021 Mar 23.

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.

Emerging retrospective and prospective studies indicate that immune checkpoint inhibitors (ICIs) can be safe and effective cancer treatments among people living with human immunodeficiency virus (PLWH), however this high-cancer-risk population has often been excluded from groundbreaking cancer ICI trials. Our study aimed to characterize the current rate of exclusion and conditional inclusion of PLWH in cancer ICI trials by tumor type, trial phase, and year. ClinicalTrials.gov cancer ICI trials with planned starts between 1/1/2019 and 10/20/2020 were identified. Based on trial eligibility criteria, trials were categorized as "excluded" if PLWH could not enroll, "conditionally included" if only PLWH with adequate immune function were allowed, or "included/not specified" if HIV was not mentioned in the eligibility criteria. Trials from 2014 were separately collected for comparison over time. The number of trials excluding PLWH were compared to the included/not specified group using Fisher's exact test. Of 809 trials analyzed from 2019 to 2020, 74.4% excluded, 6.9% conditionally included, and 18.7% included/did not specify PLWH. Early phase trials excluded PLWH more frequently than late phase trials. The 2019-2020 trial cohort showed no significant change in exclusion of PLWH compared to 2014. Despite increasing evidence for safe and effective ICI use for PLWH, most cancer ICI trials exclude PLWH and few studies permit PLWH to participate, even if HIV is well-controlled.
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http://dx.doi.org/10.1038/s41598-021-86081-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988004PMC
March 2021

Association between smoking history and tumor mutation burden in advanced non-small cell lung cancer.

Cancer Res 2021 Mar 2. Epub 2021 Mar 2.

Environmental Health, Harvard School of Public Health

Lung carcinogenesis is a complex and stepwise process involving accumulation of genetic mutations in signaling and oncogenic pathways via interactions with environmental factors and host susceptibility. Tobacco exposure is the leading cause of lung cancer, but its relationship to clinically relevant mutations and the composite tumor mutation burden (TMB) has not been fully elucidated. In this study, we investigated the dose-response relationship in a retrospective observational study of 931 patients treated for advanced stage non-small cell lung cancer (NSCLC) between April 2013 and February 2020 at the Dana Farber Cancer Institute and Brigham and Women's Hospital. Doubling smoking pack-years was associated with increased KRASG12C mutations and less frequent EGFRdel19 and EGFRL858R mutations, while doubling smoking-free months was associated with more frequent EGFRL858R. In advanced lung adenocarcinoma, doubling smoking pack-years was associated with an increase in TMB, while doubling smoking-free months was associated with a decrease in TMB, after controlling for age, gender and stage. There is a significant dose-response association of smoking history with genetic alterations in cancer-related pathways and tumor mutation burden in advanced lung adenocarcinoma.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3991DOI Listing
March 2021

Whole exome sequencing (WES) analysis of transformed small cell lung cancer (SCLC) from lung adenocarcinoma (LUAD).

Transl Lung Cancer Res 2020 Dec;9(6):2428-2439

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Histologic transformation of non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a rare mechanism of acquired resistance to epidermal growth factor receptor ()-targeted tyrosine kinase inhibitors. However, the SCLC transformation has also been observed in non.

Egfr: mutant NSCLC. In these cases, whether SCLC initially co-exists with NSCLC or originates from initial NSCLC remains to be determined.

Methods: Whole exome sequencing was performed on 10 samples from 5 patients with SCLC transformation from lung adenocarcinoma (LUAD), a main subtype of NSCLC. Somatic mutations and copy number variations (CNVs) were analyzed to explore the differences between initial LUAD and transformed SCLC, as well as the origin of transformed SCLC.

Results: After SCLC transformation, the mutation spectrum changed, with decreased C>T and increased C>A. Compared with initial LUAD, the CNV burden of transformed SCLC was greatly increased (39.0 . 61.1, Wilcoxon P=0.4). The higher the CNV burden of LUAD, the shorter the time to SCLC transformation was observed to be; and the higher the CNV burden of transformed SCLC, the shorter the overall survival (OS) after transformation. Clonal evolution analysis showed different clonal components between initial LUAD and transformed SCLC.

Conclusions: The transformation of LUAD into SCLC may be promoted by CNV events rather than mutational events. CNV burden was associated with the time to SCLC transformation and with the OS of patients following SCLC transformation. Transformed SCLC did not evolve directly from the initial LUAD but branched off from LUAD before the time of initial diagnosis.
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http://dx.doi.org/10.21037/tlcr-20-1278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815376PMC
December 2020

What Is the Standard First-Line Treatment for Advanced Non-Small Cell Lung Cancer?

Cancer J 2020 Nov/Dec;26(6):485-495

From the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.

The initial treatment regimens for advanced non-small cell lung cancer (NSCLC) have drastically evolved over the last 15 years with the rapid development of improved genomic sequencing technologies and the emergence of immune checkpoint inhibitors. Highly active oral kinase inhibitors are now approved for several molecularly defined subsets of NSCLC, including those harboring alterations in the EGFR, ALK, ROS1, BRAF, MET, RET, and NTRK genes, although acquired resistance to these targeted therapies remains a significant clinical challenge. In lung cancers lacking targetable mutations, programmed death 1/programmed death ligand 1 immune checkpoint inhibitors, used alone or in combination with cytotoxic T-lymphocyte-associated protein 4 inhibitors and/or cytotoxic chemotherapy, have led to meaningful improvements in overall survival. With many therapeutic options available to patients, here we review the recommended frontline treatment regimens for advanced NSCLC with and without targetable genomic drivers.
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http://dx.doi.org/10.1097/PPO.0000000000000489DOI Listing
December 2020

Multisystem Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors for Treatment of Non-Small Cell Lung Cancer.

JAMA Oncol 2020 12;6(12):1952-1956

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.

Importance: The spectrum of individual immune-related adverse events (irAEs) from anti-programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) has been reported widely, and their development is associated with improved patient survival across tumor types. The spectrum and impact on survival for patients with non-small cell lung cancer (NSCLC) who develop multisystem irAEs from ICIs, has not been described.

Objective: To characterize multisystem irAEs, their association with survival, and risk factors for multisystem irAE development.

Design, Setting, And Participants: This retrospective cohort study carried out in 5 academic institutions worldwide included 623 patients with stage III/IV NSCLC, treated with anti-PD-(L)1 ICIs alone or in combination with another anticancer agent between January 2007 and January 2019.

Exposures: Anti-PD-(L)1 monotherapy or combinations.

Main Outcomes And Measures: Multisystem irAEs were characterized by combinations of individual irAEs or organ system involved, separated by ICI-monotherapy or combinations. Median progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Differences in PFS and OS between irAE groups were assessed by multivariable models. Risk for multisystem irAE was estimated as odds ratios by multivariable logistic regression.

Results: The 623 patients included in the study were mostly men (60%, n = 375) and White (77%, n = 480). The median (range) age was 66 (58-73) years, and 148 patients (24%) developed a single irAE, whereas 58 (9.3%) developed multisystem irAEs. The most common multisystem irAE patterns in patients receiving anti-PD-(L)1 monotherapy were pneumonitis thyroiditis (n = 7, 14%), hepatitis thyroiditis (n = 5, 10%), dermatitis pneumonitis (n = 5, 10%), and dermatitis thyroiditis (n = 4, 8%). Favorable Eastern Cooperative Oncology Group (ECOG) performance status (PS) (ECOG PS = 0/1 vs 2; adjusted odds ratio [aOR], 0.27; 95% CI, 0.08-0.94; P = .04) and longer ICI duration (aOR, 1.02; 95% CI, 1.01-1.03; P < .001) were independent risk factors for development of multisystem irAEs. Patients with 1 irAE and multisystem irAEs demonstrated incrementally improved OS (adjusted hazard ratios [aHRs], 0.86; 95% CI, 0.66-1.12; P = .26; and aHR, 0.57; 95% CI, 0.38-0.85; P = . 005, respectively) and PFS (aHR, 0.68; 95% CI, 0.55-0.85; P = .001; and aHR, 0.39; 95% CI, 0.28-0.55; P < .001, respectively) vs patients with no irAEs, in multivariable models adjusting for ICI duration.

Conclusions And Relevance: In this multicenter cohort study, development of multisystem irAEs was associated with improved survival in patients with advanced NSCLC treated with ICIs.
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http://dx.doi.org/10.1001/jamaoncol.2020.5012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596677PMC
December 2020

Baseline BMI and BMI variation during first line pembrolizumab in NSCLC patients with a PD-L1 expression ≥ 50%: a multicenter study with external validation.

J Immunother Cancer 2020 10;8(2)

Medical Oncology Unit, Sant'Andrea Hospital, Roma, Lazio, Italy.

Background: The association between obesity and outcomes in patients receiving programmed death-1/programmed death ligand-1 (PD-L1) checkpoint inhibitors has already been confirmed in pre-treated non-small cell lung cancer (NSCLC) patients, regardless of PD-L1 tumor expression.

Methods: We present the outcomes analysis according to baseline body mass index (BMI) and BMI variation in a large cohort of metastatic NSCLC patients with a PD-L1 expression ≥50%, receiving first line pembrolizumab. We also evaluated a control cohort of metastatic NSCLC patients treated with first line platinum-based chemotherapy. Normal weight was set as control group.

Results: 962 patients and 426 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Obese patients had a significantly higher objective response rate (ORR) (OR=1.61 (95% CI: 1.04-2.50)) in the pembrolizumab cohort, while overweight patients had a significantly lower ORR (OR=0.59 (95% CI: 0.37-0.92)) within the chemotherapy cohort. Obese patients had a significantly longer progression-free survival (PFS) (HR=0.61 (95% CI: 0.45-0.82)) in the pembrolizumab cohort. Conversely, they had a significantly shorter PFS in the chemotherapy cohort (HR=1.27 (95% CI: 1.01-1.60)). Obese patients had a significantly longer overall survival (OS) within the pembrolizumab cohort (HR=0.70 (95% CI: 0.49-0.99)), while no significant differences according to baseline BMI were found in the chemotherapy cohort. BMI variation significantly affected ORR, PFS and OS in both the pembrolizumab and the chemotherapy cohorts.

Conclusions: Baseline obesity is associated to significantly improved ORR, PFS and OS in metastatic NSCLC patients with a PD-L1 expression of ≥50%, receiving first line pembrolizumab, but not among patients treated with chemotherapy. BMI variation is also significantly related to clinical outcomes.
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http://dx.doi.org/10.1136/jitc-2020-001403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574933PMC
October 2020

Plasma IL-6 changes correlate to PD-1 inhibitor responses in NSCLC.

J Immunother Cancer 2020 10;8(2)

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Background: Blood-based biomarkers of anti-solid tumor immune checkpoint blockade (ICB) response are lacking. We hypothesized that changes in systemic cytokine levels with the initial doses of programmed cell death protein 1 (PD-1) pathway inhibitors would correlate with clinical responses. New ultrasensitive ELISA technology enables quantitation of plasma proteins in sub-picogram-per-milliliter concentrations.

Methods: We measured plasma cytokines by ultrasensitive single-molecule array assays in patients with non-small-cell lung carcinoma before and during treatment with anti-PD-1 therapy. Association with best overall response and progression-free survival (PFS) was assessed by Kruskall-Wallis test and Kaplan-Meier plots with log-rank test, respectively.

Results: A decrease in interleukin 6 (IL-6) levels was associated with improved PFS (n=47 patients, median PFS: 11 vs 4 months, HR 0.45 (95% CI 0.23 to 0.89), p=0.04). The extent of change in IL-6 differed between best overall response categories (p=0.01) and correlated with changes in C reactive protein levels. We also explored plasma cytokine levels in relation to immune-related adverse effects and observed some correlation.

Conclusions: This study suggests the presence of a systemic, proteomic reflection of successful ICB outside the tumor microenvironment with plasma decreases in IL-6 and CRP.
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http://dx.doi.org/10.1136/jitc-2020-000678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537334PMC
October 2020

Immune-related adverse events on body CT in patients with small-cell lung cancer treated with immune-checkpoint inhibitors.

Eur J Radiol 2020 Nov 10;132:109275. Epub 2020 Sep 10.

Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA; Department of Radiology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. Electronic address:

Purpose: Investigate the incidence and imaging characteristics of radiologically-evident immune-related adverse events (irAEs) on body CT in patients with small-cell lung cancer (SCLC) treated with immune-checkpoint inhibitors.

Methods: The study included 53 patients with relapsed/refractory SCLC (27 men, 26 women) treated with PD-1/PD-L1 inhibitors alone or in combination with CTLA-4 inhibition, who had baseline and at least one follow-up body CT during therapy. Body CT scans were reviewed to detect and characterize organ-specific irAEs including thyroiditis, pneumonitis, hepatitis, pancreatitis, enteritis, and colitis.

Results: Nineteen patients (36 %) developed radiologically-evident irAEs. The median time from therapy initiation to irAE onset was 7.1 weeks. Pneumonitis and colitis were most common, noted in 9 patients (17 %) each. Seven colitis cases demonstrated pancolitis, and two cases showed segmental colitis associated with diverticulosis. The common radiographic patterns of pneumonitis were acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) pattern (n = 4) and cryptogenic organizing pneumonia (COP) pattern (n = 3). Other irAEs included thyroiditis (n = 3), enteritis (n = 2), hepatitis (n = 1), and pancreatitis (n = 1). Older age (p = 0.03) and prior radiotherapy to any organ (p = 0.03) was associated with overall irAEs. Prior chest radiotherapy was significantly associated with pneumonitis or thyroiditis (p = 0.0004).

Conclusion: Radiologically-evident irAEs were noted on body CT in 36 % of patients with SCLC treated with immune-checkpoint inhibitors. Colitis and pneumonitis were most common. Prior chest radiotherapy was a predictor of the development of both pneumonitis and thyroiditis. Awareness of risk factors and CT findings of irAEs is important for early detection and accurate diagnosis of potentially serious immunotherapy toxicities.
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http://dx.doi.org/10.1016/j.ejrad.2020.109275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655623PMC
November 2020

Outcomes to first-line pembrolizumab in patients with PD-L1-high (≥50%) non-small cell lung cancer and a poor performance status.

J Immunother Cancer 2020 08;8(2)

Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA

Background: Patients with non-small cell lung cancer (NSCLC) and a poor Eastern Cooperative Oncology Group Performance Status (ECOG PS) have been excluded from phase III immunotherapy clinical trials. We sought to evaluate clinical outcomes to first-line pembrolizumab in patients with advanced NSCLC, a PD-L1 Tumor Proportion Score (TPS) of ≥50%, and an ECOG PS of 2.

Methods: We performed a multicenter retrospective analysis of patients with metastatic NSCLC and a PD-L1 TPS of ≥50% (negative for genomic alterations in and ) who received treatment with first-line pembrolizumab. Clinical outcomes were compared in patients based on ECOG PS.

Results: Among the 234 patients, 83.3% (n=195) had an ECOG PS of 0 or 1, and 16.7% (n=39) had an ECOG PS of 2. The baseline clinicopathological characteristics were balanced between the ECOG PS 0-1 vs 2 groups in terms of age, sex, tobacco use, histology, mutation status, presence of other potentially targetable driver mutations (), presence of brain metastases, and PD-L1 TPS distribution. Compared with patients with an ECOG PS of 0 or 1, patients with an ECOG PS of 2 had a significantly lower objective response rate (43.1% vs 25.6%; p=0.04), a numerically shorter median progression-free survival (6.6 months vs 4.0 months; HR 0.70 (95% CI 0.47 to 1.06); p=0.09), and a significantly shorter median overall survival (20.3 months vs 7.4 months; HR 0.42 (95% CI 0.26 to 0.68); p<0.001). On disease progression, patients with an ECOG PS of 2 were significantly less likely to receive second-line systemic therapy compared with patients with an ECOG PS of 0-1 (65% vs 22.2%, p=0.001).

Conclusions: A subset of patients with NSCLC and an ECOG PS of 2 can respond to first-line pembrolizumab. However, clinical outcomes in this population are often poor and use of second-line systemic therapy is infrequent.
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http://dx.doi.org/10.1136/jitc-2020-001007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406027PMC
August 2020

Immune-related Adverse Events of Pembrolizumab in a Large Real-world Cohort of Patients With NSCLC With a PD-L1 Expression ≥ 50% and Their Relationship With Clinical Outcomes.

Clin Lung Cancer 2020 11 21;21(6):498-508.e2. Epub 2020 Jun 21.

Department of Oncology, Macerata Hospital, Macerata, Italy.

Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%.

Patients And Methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes.

Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival.

Conclusions: This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting.
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http://dx.doi.org/10.1016/j.cllc.2020.06.010DOI Listing
November 2020

Targeting DNA damage response and repair genes to enhance anticancer immunotherapy: rationale and clinical implication.

Future Oncol 2020 Aug 15;16(23):1751-1766. Epub 2020 Jun 15.

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

DNA damage response and repair () genes play a central role in the life of actively replicating cells, cooperating to maintenance of genomic integrity. However, exogenous or endogenous factors, including deficiency in genes, can cause different degrees of DNA damage that profoundly impacts the tumor immunogenicity and enhance antitumor immune response through neoantigen-dependent and neoantigen-independent mechanisms. Inhibition of DDRs is already an effective therapeutic strategy in different cancer types. In addition, because DDR inhibition can also induce and amplify DNA damage in cancer cells, with a deep impact on antitumor immune responses, combining DDR inhibitors with immune checkpoint inhibitors represent an attractive therapeutic strategy to potentially improve the clinical outcomes of patients with metastatic cancer. In this review, we provide an overview of the rational and potential of combining DDR and immune checkpoint inhibition to exploit the enhanced antitumor immune response induced by DNA damage.
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http://dx.doi.org/10.2217/fon-2020-0215DOI Listing
August 2020

Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50.

Cancer Immunol Immunother 2020 Nov 30;69(11):2209-2221. Epub 2020 May 30.

Medical Oncology, F. Spaziani Hospital, Frosinone, Italy.

Background: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%.

Methods: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%.

Results: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis.

Conclusion: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.
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http://dx.doi.org/10.1007/s00262-020-02613-9DOI Listing
November 2020

Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: A multicentre study.

Eur J Cancer 2020 07 23;134:19-28. Epub 2020 May 23.

Department of Medical, Oral and Biotechnological Sciences, University G. D'Annunzio, Chieti-Pescara, Italy.

Background: Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICIs) are lacking.

Methods: We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in patients with advanced cancer. IrAEs were categorized into 'early' (≤12 months) and 'late' (>12 months).

Results: From September 2013 to October 2019, 436 consecutive patients were evaluated. Two hundred twenty-three experienced any grade early-irAEs (51.1%), whereas 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, whereas 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced GIII/GIV irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95% confidence interval [CI]: 2.8-4.2), whereas the median time to onset of late-irAEs was 16.6 months (95% CI: 15.8-17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (hazard ratio [HR] = 0.63 [95% CI: 0.30-1.29], p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 [95% CI: 0.37-1.56], p = 0.452). In addition, the time-adjusted cumulative risk of death in accordance with both early-irAEs (HR = 0.79 [95% CI: 0.34-1.86], p = 0.598) and late-irAEs (HR = 0.92 [95% CI: 0.49-1.74], p = 0.811) did not show statistically significant differences.

Conclusion: Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs.
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http://dx.doi.org/10.1016/j.ejca.2020.04.025DOI Listing
July 2020

Safety and efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer and hepatitis B or hepatitis C infection.

Lung Cancer 2020 07 24;145:181-185. Epub 2020 Feb 24.

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States. Electronic address:

Objectives: The safety and efficacy of immunotherapy among patients with history of hepatitis B (HBV) or hepatitis C virus (HCV) infection and non-small cell lung cancer (NSCLC) remains unclear as this population has traditionally been excluded from clinical trials with immune checkpoint inhibitors (ICIs).

Materials And Methods: We retrospectively evaluated treatment toxicities and clinical outcomes in nineteen patients with NSCLC and history of past or chronic HBV (16 cases, two of these had HCV co-infection) or chronic HCV infection (five cases), who received a programmed death-1 (PD-1) pathway inhibitor.

Results: The overall response rate to immunotherapy was 35 %, and the median progression-free survival was 4.5 months. After ICI initiation, increases in liver function tests (LFTs) from baseline were infrequent and mild, and no patients experienced grade 3 or 4 hepatic immune-related adverse events or required ICI discontinuation or corticosteroid administration for management of hepatic toxicity. There were no significant changes in viral load or cases of HBV reactivation or HCV flare while on ICI therapy.

Conclusion: In this case series, treatment with immunotherapy in patients with NSCLC and past or chronic viral hepatitis appears to be safe, and responses to ICIs can be durable in this population. Additional studies are needed in larger cohorts of patients to determine the safety of immunotherapy in patients with chronic viral infections.
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http://dx.doi.org/10.1016/j.lungcan.2020.02.013DOI Listing
July 2020

Treatment Patterns and Clinical Outcomes Among Patients With ROS1-rearranged Non-small-cell Lung Cancer Progressing on Crizotinib.

Clin Lung Cancer 2020 09 15;21(5):e478-e487. Epub 2020 Apr 15.

Medical Oncology, Santa Maria della Misericordia Hospital, University of Perugia, Piazzale Menghini, Perugia, Italy. Electronic address:

Background: ROS1 rearrangements define a subset of non-small-cell lung cancers (NSCLCs) that are susceptible to therapeutic ROS1 kinase inhibition. Despite the fact that most patients initially respond to the first-generation ROS1 tyrosine kinase inhibitor (TKI) crizotinib, relapse invariably occurs, and therapeutic options upon disease progression are limited.

Patients And Methods: We conducted a multicenter study of patients with ROS1-rearranged NSCLC who progressed on ROS1 TKIs and examined the clinical outcomes based on the post-progression treatment approaches.

Results: Among 29 patients with ROS1-rearrangement who received at least 1 ROS1 inhibitor, the median age was 51 years (range, 30-80 years), 70.8% of patients were female, and 68.9% were never-smokers. Upon progression to the first TKI, 11 patients (37.9%) received treatment with TKIs beyond progression. The median second progression-free survival to TKIs in patents treated beyond progression was 5.5 months (95% confidence interval [CI], 4.1-9.1 months), whereas the post-progression survival was 21.0 months (95% CI, 5.5 months-not reached [NR]). Eleven (37.9%) patients received a sequential treatment with lorlatinib ROS1 TKIs following a first generation ROS1 TKI. The overall response rate, median progression-free survival, and median overall survival (OS) to next-generation TKIs were 41.7% (95% CI, 15.2%-72.3%), 12.7 months (95% CI, 8.5 months-NR), and 17.0 months (95% CI, 15.8 months-NR), respectively. Patients treated with sequential ROS1 TKIs had a significantly longer median OS compared with those who were not (NR vs. 16.1 months; hazard ratio, 0.26; 95% CI, 0.10-0.78; P = .017).

Conclusion: In this study, we reported that a subset of patients with ROS1-rearranged NSCLC may benefit from treatment with TKIs beyond progression and that sequential treatment with crizotinib followed by lorlatinib is associated with improved OS in patients with ROS1-rearranged NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2020.03.008DOI Listing
September 2020

Correction to: Outcomes associated with immune-related adverse events in metastatic non-small cell lung cancer treated with nivolumab: a pooled exploratory analysis from a global cohort.

Cancer Immunol Immunother 2020 07;69(7):1189

Division of Hematology/Oncology, Department of Internal Medicine, East Carolina University, Greenville, NC, USA.

The original version of this article unfortunately contained a mistake. The second sentence of the section "irAEs and ICI efficacy" should read as.
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http://dx.doi.org/10.1007/s00262-020-02582-zDOI Listing
July 2020

Impact of DNA Damage Response and Repair (DDR) Gene Mutations on Efficacy of PD-(L)1 Immune Checkpoint Inhibition in Non-Small Cell Lung Cancer.

Clin Cancer Res 2020 08 24;26(15):4135-4142. Epub 2020 Apr 24.

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Purpose: DNA damage response and repair (DDR) gene alterations are associated with increased tumor-infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with clinical outcomes to programmed death ligand 1 [PD-(L)1] blockade in non-small cell lung cancer (NSCLC) is unknown.

Experimental Design: Tumors from patients treated with PD-(L)1 inhibitors were analyzed using targeted next-generation sequencing (NGS). Cancers were categorized on the basis of the presence or absence of deleterious mutations across a panel of 53 DDR genes. Clinical outcomes to PD-(L)1 inhibitors were evaluated according to DDR mutation status.

Results: Of 266 patients with successful NGS who received PD-(L)1 inhibitors, 132 (49.6%) were identified as having deleterious DDR mutations (DDR-positive). DDR-positive and DDR-negative groups were similar in terms of baseline clinicopathologic characteristics. The median TMB was significantly higher in the DDR-positive group compared with the DDR-negative group (12.1 vs. 7.6 mutations/megabase; < 0.001). Compared with DDR-negative patients ( = 134), DDR-positive patients had a significantly higher objective response rate (30.3% vs. 17.2%; = 0.01), longer median progression-free survival [PFS; 5.4 vs. 2.2 months; HR, 0.58 (95% confidence interval (CI), 0.45-0.76); < 0.001], and longer median overall survival [OS; 18.8 vs. 9.9 months; HR, 0.57 (95% CI, 0.42-0.77); < 0.001] with PD-(L)1 therapy. After adjusting for PD-L1, TMB, performance status, tobacco use, and line of therapy, DDR-positive status was associated with a significantly longer PFS [HR, 0.68 (95% CI, 0.51-0.92); = 0.01] and OS [HR, 0.60 (95% CI, 0.43-0.85); = 0.004] in multivariate analysis.

Conclusions: Deleterious DDR mutations are frequent in NSCLC and are associated with improved clinical outcomes in patients with NSCLC treated with PD-(L)1 blockade.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3529DOI Listing
August 2020

Outcomes associated with immune-related adverse events in metastatic non-small cell lung cancer treated with nivolumab: a pooled exploratory analysis from a global cohort.

Cancer Immunol Immunother 2020 Jul 5;69(7):1177-1187. Epub 2020 Mar 5.

Division of Hematology/Oncology, Department of Internal Medicine, East Carolina University, Greenville, NC, USA.

Background: Immune-related adverse events (irAEs) comprise a distinct spectrum of auto-inflammatory manifestations triggered due to immune checkpoint inhibitors (ICI). Current data on the association of irAEs with outcomes in NSCLC treated with nivolumab are limited.

Methods And Objectives: We pooled data from 531 metastatic NSCLC patients from five centers treated with nivolumab after failing platinum-based chemotherapy. The primary objective was to investigate the relationship between irAEs with clinical benefit to nivolumab as well as to elucidate patterns of irAE-related ICI discontinuations and their impact on survival.

Results: 33.0% (173/531) of patients treated with nivolumab were noted to have an irAE. Patients with irAEs had a significantly longer median PFS [6.1 vs. 3.1 months, HR 0.68 95% CI (0.55-0.85); p = 0.001] and OS [14.9 vs. 7.4 months, HR 0.66 95% CI (0.52-0.82); p < 0.001)] compared to those without irAEs. In multivariate analysis, the presence of irAEs showed a significantly better PFS [HR 0.69, 95% CI (0.55-0.87); p = 0.002] and a trend for better OS [HR 0.62, 95% CI (0.55-1.03); p = 0.057]. Patients with permanent ICI discontinuation secondary to index irAE had a significantly shorter median PFS [2.3 vs. 6.6 months, HR 1.74 95% CI (1.06-2.80); p = 0.02] and median OS [3.6 vs. 17.6 months; HR 2.61 95% CI (1.61-4.21); p < 0.001] compared to those that did not have permanent ICI discontinuation.

Conclusions: Our pooled exploratory analysis demonstrates improved clinical benefit to nivolumab in NSCLC patients experiencing irAEs. We also observed negative impact of irAE-related treatment discontinuation on survival in this group of patients.
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http://dx.doi.org/10.1007/s00262-020-02536-5DOI Listing
July 2020

Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving programmed cell death protein-1 (PD-1)/ Programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors: A multicentre analysis of immune-related adverse events.

Eur J Cancer 2020 03 5;128:17-26. Epub 2020 Mar 5.

Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy.

Background: Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients.

Patients And Methods: We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI.

Results: One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21-92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6-46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events [irAEs] (p < 0.0001), G3/G4 irAEs (p < 0.0001) and irAEs leading to discontinuation (LTD) (p < 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5-14.9 for overweight, and 16.6 (95%CI: 10.3-26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 [95%CI: 6.4-22.3], p < 0.0001) and LTD irAEs (OR = 8.8 [95%CI: 4.3-18.2], p < 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients.

Conclusions: Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.
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http://dx.doi.org/10.1016/j.ejca.2019.12.031DOI Listing
March 2020

Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14-Mutant NSCLC.

Clin Cancer Res 2020 06 7;26(11):2615-2625. Epub 2020 Feb 7.

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Purpose: Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKI) are poorly understood. We aimed to characterize the genomic mechanisms of resistance to type I and type II MET TKIs and their impact on sequential MET TKI therapy outcomes in patients with metastatic exon 14-mutant NSCLC.

Experimental Design: Genomic alterations occurring at the time of progression on MET TKIs were studied using plasma and tissue next-generation sequencing (NGS).

Results: A total of 20 patients had tissue or plasma available for analysis at the time of acquired resistance to a MET TKI. Genomic alterations known or suspected to be mechanisms of resistance were detected in 15 patients (75%). On-target acquired mechanisms of resistance, including single and polyclonal kinase domain mutations in codons H1094, G1163, L1195, D1228, Y1230, and high levels of amplification of the exon 14-mutant allele, were observed in 7 patients (35%). A number of off-target mechanisms of resistance were detected in 9 patients (45%), including mutations and amplifications in , and ; one case displayed both on- and off-target mechanisms of resistance. In 2 patients with on-target resistant mutations, switching between type I and type II MET TKIs resulted in second partial responses.

Conclusions: On-target secondary mutations and activation of bypass signaling drive resistance to MET TKIs. A deeper understanding of these molecular mechanisms can support the development of sequential or combinatorial therapeutic strategies to overcome resistance.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3608DOI Listing
June 2020

Antibody-drug conjugates for lung cancer in the era of personalized oncology.

Semin Cancer Biol 2021 Feb 30;69:268-278. Epub 2019 Dec 30.

Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, 06129, Italy. Electronic address:

With 9.6 million deaths in 2018, cancer represents one of the most common causes of death, both in men and women. Despite recent advances in the understanding of molecular mechanisms involved in cancer development and progression, treatment options are still limited. Limitations of traditional chemotherapy include the lack of selectivity and the unfavorable safety profile. The efficacy of targeted therapies (e.g., tyrosine kinase inhibitors) is also limited by their cytostatic action, which inhibits tumor cell proliferation without inducing tumor cell death, and by the risk of acquired resistance. Antibody-drug conjugates (ADCs), a newly developed class of engineered anticancer drugs, consist of recombinant monoclonal antibodies against tumor-specific antigens that are covalently bound to cytotoxic agents. They have been designed to overcome the limitations of traditional chemotherapy and targeted therapies by combining the target selectivity of monoclonal antibodies with the high potency of cytotoxic drugs. Currently, ADCs that have received regulatory approval include brentuximab vedotin for CD30-positive Hodgkin lymphoma and trastuzumab emtansine for human epidermal growth factor receptor 2-positive breast cancer. However, over 80 novel ADCs are actively being investigated in preclinical studies and early-phase clinical trials. In this review, we will provide a comprehensive overview of the biological rational, efficacy and safety of ADCs as therapeutic agents against non-small cell lung cancer and small cell lung cancer.
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http://dx.doi.org/10.1016/j.semcancer.2019.12.024DOI Listing
February 2021

Immune-related adverse events correlate with clinical outcomes in NSCLC patients treated with nivolumab: The Italian NSCLC expanded access program.

Lung Cancer 2020 02 20;140:59-64. Epub 2019 Dec 20.

Biostatistical Unit, Regina Elena National Cancer Institute, IRCCS, Rome, Italy.

Objectives: The incidence of any and of severe-grade immune-related adverse events (irAEs) with second-line nivolumab monotherapy is 31-65 % and 2-5 % respectively. While potentially serious and even fatal, in the absence of an appropriate therapy, such events might be indicators of the activation of the immune system and, potentially, of efficacy.

Materials And Methods: We collected the records of 1959 non-small-cell lung cancer (NSCLC) patients treated with nivolumab in the Italian expanded access program, and we registered the appearance of any and of severe grade irAEs. We retrospectively searched for correlations between toxicity and efficacy parameters by using Cox's regression analysis.

Results: Overall, 342 (17.8%) patients developed an irAE of any grade. We observed that patients developing irAE of any grade achieved a significantly higher response rate (RR 27.2% vs 15.2%; p < 0.0001), disease control rate (DCR 60.5% vs 40.2%; p < 0.0001), median progression-free survival (mPFS 6.0 months [95% CI 4.9-7.1] vs 3.0 [95% CI: 2.8-3.2], p < 0.0001) and median overall survival (mOS 16.7 months [95% CI: 13.5-19.9] vs 9.4 [95% CI: 8.4-10.4], p < 0.00001) compared to patients who did not. At multivariate analysis the development of an irAE remained an independent indicator of nivolumab efficacy (HR 1.44 [95% CI: 1.22-1.71] p < 0.0001).

Conclusions: This report, performed in Caucasian NSCLC patients, showed that the appearance of irAEs correlated with outcome.
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http://dx.doi.org/10.1016/j.lungcan.2019.12.014DOI Listing
February 2020

Harmonization of Tumor Mutational Burden Quantification and Association With Response to Immune Checkpoint Blockade in Non-Small-Cell Lung Cancer.

JCO Precis Oncol 2019 12;3. Epub 2019 Nov 12.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: Heterogeneity in tumor mutational burden (TMB) quantification across sequencing platforms limits the application and further study of this potential biomarker of response to immune checkpoint inhibitors (ICI). We hypothesized that harmonization of TMB across platforms would enable integration of distinct clinical datasets to better characterize the association between TMB and ICI response.

Methods: Cohorts of NSCLC patients sequenced by one of three targeted panels or by whole exome sequencing (WES) were compared (total n=7297). TMB was calculated uniformly and compared across cohorts. TMB distributions were harmonized by applying a normal transformation followed by standardization to z-scores. In sub-cohorts of patients treated with ICIs (DFCI n=272; MSKCC n=227), the association between TMB and outcome was assessed. Durable clinical benefit (DCB) was defined as responsive/stable disease lasting ≥6 months.

Results: TMB values were higher in the panel cohorts than the WES cohort. Average mutation rates per gene were highly concordant across cohorts (Pearson coefficient 0.842-0.866). Subsetting the WES cohort by gene panels only partially reproduced the observed differences in TMB. Standardization of TMB into z-scores harmonized TMB distributions and enabled integration of the ICI-treated sub-cohorts. Simulations indicated that cohorts >900 are necessary for this approach. TMB did not associate with response in never smokers or patients harboring targetable driver alterations, although these analyses were under-powered. Increasing TMB thresholds increased DCB rate, but DCB rates within deciles varied. Receiver operator curves yielded an area under the curve of 0.614 with no natural inflection point.

Conclusion: Z-score conversion harmonizes TMB values and enables integration of datasets derived from different sequencing panels. Clinical and biologic features may provide context to the clinical application of TMB, and warrant further study.
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http://dx.doi.org/10.1200/PO.19.00171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907021PMC
November 2019

Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease.

J Clin Oncol 2020 02 4;38(6):576-583. Epub 2019 Dec 4.

The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: The risk of immune checkpoint inhibitor therapy-related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events in patients with underlying IBD who received immune checkpoint inhibitors.

Patients And Methods: We performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events.

Results: Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn's disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; < .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event-related deaths were recorded. Anti-cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48; = .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53; = .058, respectively).

Conclusion: Preexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.
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http://dx.doi.org/10.1200/JCO.19.01674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030892PMC
February 2020

Impact of performance status and age on osimertinib efficacy in patients with -mutant T790M-positive non-small-cell lung cancer.

J Thorac Dis 2019 Sep;11(Suppl 15):S1831-S1834

Thoracic Oncology Unit, Santa Maria della Misericordia Hospital, University of Perugia, Piazzale Menghini, Perugia, Italy.

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http://dx.doi.org/10.21037/jtd.2019.08.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783754PMC
September 2019