First-Line Nivolumab and Relatlimab Plus Chemotherapy for Gastric or Gastroesophageal Junction Adenocarcinoma: The Phase II RELATIVITY-060 Study.

PURPOSE: Open-label phase II study (RELATIVITY-060) to investigate the efficacy and safety of first-line nivolumab, a PD-1-blocking antibody, plus relatlimab, a lymphocyte-activation gene 3 (LAG-3)-blocking antibody, plus chemotherapy in patients with previously untreated advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC). METHODS: Patients with unresectable, locally advanced or metastatic GC/GEJC were randomly assigned 1:1 to nivolumab + relatlimab (fixed-dose combination) + chemotherapy or nivolumab + chemotherapy. The primary end point was objective response rate (ORR; per RECIST v1.1 by blinded independent central review [BICR]) in patients whose tumors had LAG-3 expression ≥1%. RESULTS: Of 274 patients, 138 were randomly assigned to nivolumab + relatlimab + chemotherapy and 136 to nivolumab + chemotherapy. Median follow-up was 11.9 months. In patients with LAG-3 expression ≥1%, BICR-assessed ORR (95% CI) was 48% (38 to 59) in the nivolumab + relatlimab + chemotherapy arm and 61% (51 to 71) in the nivolumab + chemotherapy arm; median progression-free survival (95% CI) by BICR was 7.0 months (5.8 to 8.4) versus 8.3 months (6.9 to 12.1; hazard ratio [HR], 1.41 [95% CI, 0.97 to 2.05]), and median overall survival (95% CI) was 13.5 months (11.9 to 19.1) versus 16.0 months (10.9 to not estimable; HR, 1.04 [95% CI, 0.70 to 1.54]), respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 69% and 61% of all treated patients, and 42% and 36% of patients discontinued because of any-grade TRAEs in the nivolumab + relatlimab + chemotherapy and nivolumab + chemotherapy arms, respectively. CONCLUSION: RELATIVITY-060 did not meet its primary end point of improved ORR in patients with LAG-3 expression ≥1% when relatlimab was added to nivolumab + chemotherapy compared with nivolumab + chemotherapy. Further studies are needed to address whether adding anti-LAG-3 to anti-PD-1 plus chemotherapy can benefit specific GC/GEJC patient subgroups.

Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

BACKGROUND: The prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is poor. Glofitamab is a bispecific antibody that recruits T cells to tumor cells. METHODS: In the phase 2 part of a phase 1-2 study, we enrolled patients with relapsed or refractory DLBCL who had received at least two lines of therapy previously. Patients received pretreatment with obinutuzumab to mitigate cytokine release syndrome, followed by fixed-duration glofitamab monotherapy (12 cycles total). The primary end point was complete response according to assessment by an independent review committee. Key secondary end points included duration of response, survival, and safety. RESULTS: Of the 155 patients who were enrolled, 154 received at least one dose of any study treatment (obinutuzumab or glofitamab). At a median follow-up of 12.6 months, 39% (95% confidence interval [CI], 32 to 48) of the patients had a complete response according to independent review. Results were consistent among the 52 patients who had previously received chimeric antigen receptor T-cell therapy (35% of whom had a complete response). The median time to a complete response was 42 days (95% CI, 42 to 44). The majority (78%) of complete responses were ongoing at 12 months. The 12-month progression-free survival was 37% (95% CI, 28 to 46). Discontinuation of glofitamab due to adverse events occurred in 9% of the patients. The most common adverse event was cytokine release syndrome (in 63% of the patients). Adverse events of grade 3 or higher occurred in 62% of the patients, with grade 3 or higher cytokine release syndrome in 4% and grade 3 or higher neurologic events in 3%. CONCLUSIONS: Glofitamab therapy was effective for DLBCL. More than half the patients had an adverse event of grade 3 or 4. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT03075696.).

Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial.

PURPOSE: Glofitamab is a T-cell-engaging bispecific antibody possessing a novel 2:1 structure with bivalency for CD20 on B cells and monovalency for CD3 on T cells. This phase I study evaluated glofitamab in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Data for single-agent glofitamab, with obinutuzumab pretreatment (Gpt) to reduce toxicity, are presented. METHODS: Seven days before the first dose of glofitamab (0.005-30 mg), all patients received 1,000 mg Gpt. Dose-escalation steps were determined using a Bayesian continuous reassessment method with overdose control. Primary end points were safety, pharmacokinetics, and the maximum tolerated dose of glofitamab. RESULTS: Following initial single-patient cohorts, 171 patients were treated within conventional multipatient cohorts and received at least one dose of glofitamab. This trial included heavily pretreated patients with R/R B-NHL; most were refractory to prior therapy (155; 90.6%) and had received a median of three prior therapies. One hundred and twenty-seven patients (74.3%) had diffuse large B-cell lymphoma, transformed follicular lymphoma, or other aggressive histology, and the remainder had indolent lymphoma subtypes. Five (2.9%) patients withdrew from treatment because of adverse events. Cytokine release syndrome occurred in 86 of 171 (50.3%) patients (grade 3 or 4: 3.5%); two (1.2%) patients experienced grade 3, transient immune effector cell-associated neurotoxicity syndrome-like symptoms. The overall response rate was 53.8% (complete response [CR], 36.8%) among all doses and 65.7% (CR, 57.1%) in those dosed at the recommended phase II dose. Of 63 patients with CR, 53 (84.1%) have ongoing CR with a maximum of 27.4 months observation. CONCLUSION: In patients with predominantly refractory, aggressive B-NHL, glofitamab showed favorable activity with frequent and durable CRs and a predictable and manageable safety profile.

Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease whose prognosis is associated with clinical features, cell-of-origin and genetic aberrations. Recent integrative, multi-omic analyses had led to identifying overlapping genetic DLBCL subtypes. We used targeted massive sequencing to analyze 84 diagnostic samples from a multicenter cohort of patients with DLBCL treated with rituximab-containing therapies and a median follow-up of 6 years. The most frequently mutated genes were IGLL5 (43%), KMT2D (33.3%), CREBBP (28.6%), PIM1 (26.2%), and CARD11 (22.6%). Mutations in CD79B were associated with a higher risk of relapse after treatment, whereas patients with mutations in CD79B, ETS1, and CD58 had a significantly shorter survival. Based on the new genetic DLBCL classifications, we tested and validated a simplified method to classify samples in five genetic subtypes analyzing the mutational status of 26 genes and BCL2 and BCL6 translocations. We propose a two-step genetic DLBCL classifier (2-S), integrating the most significant features from previous algorithms, to classify the samples as N12-S, EZB2-S, MCD2-S, BN22-S, and ST22-S groups. We determined its sensitivity and specificity, compared with the other established algorithms, and evaluated its clinical impact. The results showed that ST22-S is the group with the best clinical outcome and N12-S, the more aggressive one. EZB2-S identified a subgroup with a worse prognosis among GCB-DLBLC cases.

Unraveling transformation of follicular lymphoma to diffuse large B-cell lymphoma.

Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B, GNA13 and POU2AF1, which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo-diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2, DTX1, UBE2A and HIST1H1E. The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.

Long-term follow up of Hodgkin lymphoma.

BACKGROUND: Hodgkin lymphoma (HL) is the paradigm of curable disease. This study analyzed the overall survival (OS) of patients with HL and compared their survival between decades and with the expected survival of a general population. RESULTS: The median follow-up was 22 years. The median OS was 33 years. The incidence mortality rate for all causes is 2 per every 100 patients per year. The OS of our cohort at 10 years from diagnosis was 76% (95% CI: 72-79) and 52% at 30 years (95% CI: 48-57). Overall SMR (1980-2013) was 2,943 (95% CI: 2,518-3,439). Excluding the primary tumor as the cause of death, the SMR obtained is 2,266 (95% CI: 1,895-2,710). The SMR for those patients diagnosed before the year 2000 was 2,097 (95% CI: 1,732-2,539); and for those diagnosed after 2000 was 5,218 (95% CI: 8,655). The group of patients diagnosed after 2000 had statistically significant more advanced stages, were older and less responsive to treatment. CONCLUSIONS: Despite the advances achieved, the risk of death remains higher than in the general population, mainly for those patients diagnosed after year 2000, even after almost 40 years of follow-up. This data might suggest a shift to more aggressive forms of disease in recent years. PATIENTS AND METHODS: A total of 595 patients diagnosed with HL were included between January 1966 and February 2014. The standardized mortality ratio (SMR) was analyzed using the annual rate of mortality in the general Spanish population, adjusted for age, sex and time period.

Prognostic value of quantitative ctDNA levels in non small cell lung cancer patients.

BACKGROUND: Circulating tumor DNA (ctDNA) levels correlate well with tumor bulk. In this paper we aim to estimate the prognostic value of the dynamic quantification of ctDNA levels. MATERIALS AND METHODS: A total of 251 serial plasma samples from 41 non-small-cell lung cancer patients who carried an activating EGFR mutation were analysed by digital PCR. For survival analysis, ctDNA levels were computed as a time-dependent covariate. RESULTS: Dynamic ctDNA measurements had prognostic significance (hazard ratio for overall survival and progression free survival according to p.T790M mutant allele frequency; 2.676 and 2.71 respectively; P < 0.05). In the same way, patients with p.T790M-negative or unchanging or decreasing plasma levels of sensitizing EGFR mutation were 12 and 4.8 times more likely to maintain response or stable disease, respectively, than patients in which the opposite occurred (P < 0.05).On average, the p.T790M mutation was detected in plasma 51 days before the assessment of progression disease by CT-scan. Finally, ctDNA outperformed CTCs for assessing tumor progression (P = 0.021). CONCLUSIONS: The appearance or increase in a unit of the p.T790M allele frequency almost triples the risk of death and progression. This information can be used to design clinical trials aiming to estimate whether T790M positive patients should start second line treatment based on molecular data rather than imaging data.

Lung cancer in lung transplantation: incidence and outcome.

INTRODUCTION: Malignancies are one of the causes of mortality after lung transplantation. However, little is known about lung cancer outcome after lung transplantation. METHODS: We performed a retrospective search of the lung transplantation database at our institution to identify patients diagnosed with lung cancer after lung transplantation. RESULTS: Out of 633 lung transplant patients, lung cancer was detected in 23 of them (3.63%). The most common causes for transplantation were idiopathic pulmonary fibrosis (47.8%) and emphysema (43.4%). A total of 18 patients were diagnosed during follow-up, 12 cases in the native lung (52.2%) and 6 cases in the donor lung (26.1%). The diagnosis was evidenced in the explanted lung in five patients (21.7%). The median of time from transplantation to cancer diagnosis was 39.7 months (24.356.6). Lung cancer was the cause of death in 16 patients. Survival rate at1year from diagnosis of lung cancer was 45.64% (95% CI 0.2431 to 0.6473). CONCLUSIONS: Lung transplant recipients constitute a high-risk group for developing lung cancer. Among our patients, lung cancer was predominantly diagnosed in the native lung and at an advanced stage. The primary tumour was the main cause of death in most of these patients.

Concordance between circulating tumor cells and clinical status during follow-up in anaplastic lymphoma kinase (ALK) non-small-cell lung cancer patients.

BACKGROUND: The identification of anaplastic lymphoma kinase (ALK) rearrangements is found in approximately 5% of non-small-cell lung cancers (NSCLCs). However, the development of liquid biopsies as a diagnostic tool is less developed in these cases. This study investigates the use of CTCs during treatment, together with an extended follow-up to correlate with clinical evolution. PATIENTS AND METHODS: A total of 13 patients out of a cohort of 212 patients with lung adenocarcinoma, presented ALK rearrangements (6%) confirmed by tumor biopsy. A total of 60 serial blood samples were collected from these patients who were prospectively enrolled in the study. RESULTS: All patients had a positive CTC count at baseline (mean = 3). The median follow-up was 9 months (range 1-17 months). Three patients underwent surgery and their CTC counts decreased after the procedure but still remained detectable. After radiotherapy, 3 cases showed an average decrease of 5 CTCs. A total of 6 patients were treated with ALK inhibitors and a partial response was observed in 3 of them, who also presented decreased CTC counts. The other 3 patients presented primary resistance, and their CTC counts were higher than those obtained prior to progression. CONCLUSION: We believe that the use of CTCs for dynamic monitoring of NSCLC with ALK rearrangement and to detect disease persistence or recurrence may be a reliable technique. CTC counts may also have potential use to monitor the efficacy of ALK inhibitors, facilitating detection of resistance to treatment.

Dynamic circulating tumor DNA quantificaton for the individualization of non-small-cell lung cancer patients treatment.

BACKGROUND: Liquid biopsy has evolved from being a promising line to becoming a validated approach for biomarker testing. However, its utility for individualization of therapy has been scarcely reported. In this study, we show how monitoring levels of EGFR mutation in plasma can be useful for the individualization of treatment. RESULTS: Longitudinal EGFR mutation levels in plasma always correlated with tumor response ascertained by RECIST criteria. Moreover, decreasing EGFR mutation levels were detected in all patients benefiting from locoregional radiotherapy, whereas the opposite occurred when a patient progressed soon after radiotherapy treatment. Similarly, increasing EGFR mutation levels anticipated disease progression after TKI dose reduction, discontinuation of treatment, or reduced bioavailability due to drug interactions. In addition, EGFR mutation levels were useful to monitor treatment outcome of new therapies and constituted a decisive factor when the clinical situation of the patient did not correlate with responses ascertained by radiologist. Finally, our results indicate that cancer associated body fluids (pleural, pericardial or cerebrospinal fluid) are certainly a suitable source for biomarker testing that can extend EGFR mutation detection to biofluids other than blood. MATERIALS AND METHODS: A total of 180 serial plasma samples from 18 non-small-cell lung cancer patients who carried an activating EGFR mutation were investigated by digital PCR. CONCLUSIONS: Monitoring levels of EGFR mutation in plasma allows resolving doubts that frequently arise in daily clinical practice and constitutes a major step towards achieving personalized medicine.

Lung cancer as a cardiotoxic state: a review.

As the overall survival of patients with lung cancer continues to increase, more cancer survivors are faced with the risk of developing treatment-related cardiovascular toxicities. The increased knowledge of the molecular biology of non-small cell lung cancer has led to new and more personalized treatments. Nevertheless, the usual chemotherapy schemes and radiation therapy induce cardiac toxicities that are frequently underappreciated or go unnoticed. Up to date, the majority of cardiotoxicity studies have been focused in breast cancer, but new treatments in lung cancer patients, such as immune checkpoint-blocking antibodies or tyrosine kinase inhibitors, may also exert these cardiac toxic effects and therefore demand of the close collaboration of oncologists and cardiologists, in order to be addressed. The aim of this review is to provide more detailed information in regard to drug-induced cardiac toxicity focused in non-small cell lung cancer patients.

Liquid biopsy based biomarkers in non-small cell lung cancer for diagnosis and treatment monitoring.

Advances in the knowledge of the biology of non-small cell lung cancer (NSCLC) have revealed molecular information used for systemic cancer therapy targeting metastatic disease, with an important impact on patients overall survival (OS) and quality of life. However, a biopsy of overt metastases is an invasive procedure limited to certain locations and not easily acceptable in the clinic. Moreover, a single biopsy cannot reflect the clonal heterogeneity of the tumor. The analysis of peripheral blood samples of cancer patients represents a new source of cancer-derived material, known as liquid biopsy, and its components can be obtained from almost all body fluids. These components have shown to reflect characteristics of the status of both the primary and metastatic diseases, helping the clinicians to move towards a personalized medicine. The present review focuses on the liquid biopsy components: circulating tumor cells (CTCS), circulating free DNA (cfDNA), exosomes and tumor-educated platelets (TEP); the isolation technologies used and their potential use for non-invasive screening, early diagnosis, prognosis, response to treatment and real time monitoring of the disease, in NSCLC patients.

Clinical pretreatment risk factors and prediction of outcome using gallium 67 scintigraphy in patients with Hodgkin's lymphoma.

This study was conducted to investigate the prognostic effect and implications of gallium 67 scintigraphy (gallium scan) at mid-treatment and at the end of first-line treatment in patients with early- and advanced-stage Hodgkin's lymphoma (HL). A total of 216 HL patients were included in the study. Gallium scan was performed at mid-treatment and at the end of first-line treatment. The overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method. The log-rank test was used to identify univariate predictors of EFS and OS. For early-stage disease, bulky mediastinal involvement (yes vs. no, 98 vs. 79%, respectively; P=0.01), erythrocyte sedimentation rate (good vs. adverse, 98 vs. 88%, respectively; P=0.03), presence of B symptoms (no vs. yes, 94 vs. 78%, respectively; P=0.006), post-chemotherapy disease status [complete response (CR) vs. unconfirmed CR (uCR) vs. partial response (PR) vs. progressive disease (PGR), 95 vs. 90 vs. 87 vs. 0%, respectively; P<0.01] and gallium scan at mid-treatment and at the end of treatment (negative vs. positive, 88 vs. 20%, P<0.001; and 85 vs. 10%, P<0.001, respectively) significantly affected the EFS. In addition, age (<50 vs. ≥50 years, 96 vs. 78%, respectively; P=0.01), presence of B symptoms (no vs. yes, 97 vs. 87%, respectively; P=0.03), post-chemotherapy disease status (CR vs. uCR vs. PR vs. PGR, 95 vs. 90 vs. 90 vs. 0%, respectively; P<0.01) and gallium scan results at mid-treatment and at the end of treatment (negative vs. positive, 87 vs. 60%, P<0.001; and 95 vs. 0%, P<0.001, respectively) significantly affected the OS. For advanced-stage disease, Hassenclever index (1-3 vs. 4-6, 80 vs. 57%, respectively; P=0.05) and gallium scan results at mid-treatment and at the end of treatment (negative vs. positive, 84 vs. 18%, P<0.001; and 84 vs. 0%, P<0.001, respectively) significantly affected the EFS, whereas age at diagnosis (<50 vs. ≥50 years, 92 vs. 78%, respectively; P=0.04), Hassenclever index (1-3 vs. 4-6, 86 vs. 61%, respectively; P=0.04) and gallium scan results at mid-treatment and at the end of treatment (negative vs. positive, 98 vs. 40%, P<0.001; and 97 vs. 23%, P<0.001, respectively) significantly affected the OS. On the multivariate analysis, gallium scan at the end of first-line treatment retained statistical significance in terms of EFS and OS. In conclusion, post-chemotherapy gallium scan is an important prognostic factor in patients with early- or advanced-stage HL and a predictor of adverse outcome.

Sentinel lymph node biopsy in breast cancer: the role of micrometastasis.

Intraoperative sentinel lymph node biopsy is widely used in patients with early-stage breast cancer for staging the axilla. The conventional analysis of the SLN has classically been performed by frozen section or touch imprint with a rapid H&E (hematoxylin and eosin) staining. Because of the risk of false-negative results, it has been replaced by the one-step acid amplification (OSNA) assay, a molecular diagnostic assay for the detection of cytokeratin 19 mRNA expression. Due to the controversial for the use of OSNA to evaluate the SLN because of its cost-effective and the lack of consensus to perform or avoid a lymphadenectomy when there is micrometastasis, we analyze 410 patients subjected to SLN biopsy in Hospital Puerta de Hierro, Madrid (Spain). Of the total of nodes, 223 (54.4 %) were processed throughout frozen-section examination and imprint cytology and 187 (45.6 %) throughout OSNA. The specificity of the frozen-section histological examination was of 100 %, with a sensitivity of 83.33 % (95 % CI 73.07-93.60). Of the 40 patients with definitive micrometastasis in the SLN, axillary dissection was performed in 90 % of the patients, with subsequent positive affectation in four of them (11.11 %). Based on our result and taking into account that 10 % of the lymphadenectomy performed after micrometastasis are positive, we do not believe that lymphadenectomy should be avoided after N(mi+) is detected in a SLN.

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