Elizabeth Dudnik

Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases

Central nervous system (CNS) metastases occur in 30% of patients with advanced non-small cell lung cancer (NSCLC). Localized treatments targeting CNS metastases result in delays in systemic therapy administration and are associated with neurocognitive impairment. Nivolumab is an immune check-point inhibitor that is approved as a second-line treatment of NSCLC. Data regarding the intracranial activity of nivolumab is lacking. We retrospectively reviewed the efficacy and safety of nivolumab in five patients with advanced NSCLC and new/progressing intracranial metastases. Intracranial response was assessed by magnetic resonance imaging (MRI) using mRECIST v. 1.1 criteria. All patients had parenchymal brain metastases; two patients had leptomeningeal carcinomatosis diagnosed according to radiological criteria. All patients were asymptomatic and did not require corticosteroids or immediate local therapy. We observed one complete and one partial response in the brain. Stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved in one additional patient. Two patients progressed in the CNS. Time-to-response comprised 5 weeks and 9 weeks; both responses are still ongoing at the time of the report (24+ and 28+ weeks since start of treatment). Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS metastases-related grade≥3 adverse events were observed. Nivolumab might have intracranial activity and favorable safety profile in patients with CNS metastases secondary to NSCLC. Nivolumab CNS activity warrants further evaluation.

Clinical Impact of Hybrid Capture-Based Next-Generation Sequencing on Changes in Treatment Decisions in Lung Cancer.

Introduction: Targeted therapy significantly prolongs survival in lung adenocarcinoma. Current diagnostic guidelines include only EGFR and anaplastic lymphoma receptor tyrosine kinase gene (ALK) testing. Next‐generation sequencing (NGS) reveals more actionable genomic alterations than do standard diagnostic methods. Data on the influence of hybrid capture (HC)‐based NGS on treatment are limited, and we investigated its impact on treatment decisions and clinical outcomes. Methods: This retrospective study included patients with advanced lung cancer on whom HC‐based NGS was performed between November 2011 and October 2015. Demographic and clinicopathologic characteristics, treatments, and outcome data were collected. Results: A total of 101 patients were included (median age 63 years [53% females, 45% never‐smokers, and 85% with adenocarcinoma]). HC‐based NGS was performed upfront and after EGFR/ALK testing yielded negative or inconclusive results in 15% and 85% of patients, respectively. In 51.5% of patients, HC‐based NGS was performed before first‐line therapy, and in 48.5%, it was performed after treatment failure. HC‐based NGS identified clinically actionable genomic alterations in 50% of patients, most frequently in EGFR (18%), Ret proto‐oncogene (RET) (9%), ALK (8%), Mesenchymal‐epithelial transition factor (MET) receptor tyrosine kinase gene (6%), and erb‐b2 receptor tyrosine kinase 2 gene (ERBB2) (5%). In 15 patients, it identified EGFR/ALK aberrations after negative results of prior standard testing. Treatment strategy was changed for 43 patients (42.6%). The overall response rate in these patients was 65% (complete response 14.7%, partial response 50%). Median survival was not reached. Immunotherapy was administered in 33 patients, mostly without an actionable driver, with a presenting disease control rate of 32%, and with an association with tumor mutation burden. Conclusions: HC‐based NGS influenced treatment decisions in close to half of the patients with lung adenocarcinoma and was associated with an overall response rate of 65%, which may translate into a survival benefit.

RET Fusion Lung Carcinoma: Response to Therapy and Clinical Features in a Case Series of 14 Patients

Background RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B‐RET and CCDC6‐RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET‐rearranged LADC are still being delineated. Materials and Methods We present a series of 14 patients with RET‐rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy. Results A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B‐RET and CCDC6‐RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B‐RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6‐RET and KIF5B‐RET fusions showed pronounced and durable responses to platinum‐based chemotherapy that lasted for 8 to 15 months. Two patients’ tumors showed programmed cell death ligand 1‐positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months. Conclusion RET‐rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients. Micro‐Abstract Data are increasing regarding RET (rearranged during transfection) fusions in lung cancer. We present our experience with the natural history of this disease and its response to targeted therapy and standard chemotherapy in 14 patients. In our series, RET‐rearranged lung adenocarcinoma had an early disseminated presentation, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response.

ALK-Rearranged Non–Small-Cell Lung Cancer Is Associated With a High Rate of Venous Thromboembolism

Background Patients with lung cancer are at increased risk for venous thromboembolism (VTE), particularly those receiving chemotherapy. It is estimated that 8% to 15% of patients with advanced non–small‐cell lung cancer (NSCLC) experience a VTE in the course of their disease. The incidence in patients with specific molecular subtypes of NSCLC is unknown. We undertook this review to determine the incidence of VTE in patients with ALK (anaplastic lymphoma kinase)‐rearranged NSCLC. Patients and Methods We identified all patients with ALK‐rearranged NSCLC diagnosed and/or treated at the Princess Margaret Cancer Centre (PM CC) in Canada between July 2012 and January 2015. Retrospective data were extracted from electronic medical records. We then included a validation cohort comprising all consecutive patients with ALK‐rearranged NSCLC treated in 2 tertiary centers in Israel. Results Within the PM CC cohort, of 55 patients with ALK‐rearranged NSCLC, at a median follow‐up of 22 months, 23 (42%) experienced VTE. Patients with VTE were more likely to be white (P = .006). The occurrence of VTE was associated with a trend toward worse prognosis (overall survival hazard ratio = 2.88, P = .059). Within the validation cohort (n = 43), the VTE rate was 28% at a median follow‐up of 13 months. Combining the cohorts (n = 98), the VTE rate was 36%. Patients with VTE were younger (age 52 vs. 58 years, P = .04) and had a worse Eastern Cooperative Oncology Group performance status (P = .04). VTE was associated with shorter overall survival (hazard ratio = 5.71, P = .01). Conclusion The rate of VTE in our ALK‐rearranged cohort was 3‐ to 5‐fold higher than previously reported for the general NSCLC population. This warrants confirmation in larger cohorts. Micro‐Abstract We examined the rate of venous thromboembolism in a cohort of consecutive patients with ALK‐rearranged non–small‐cell lung cancer (NSCLC) at a single center and found it to be 3‐ to 5‐fold higher than previously reported in the setting of advanced NSCLC. The results were comparable when we included a validation cohort of consecutive patients at 2 other centers, with an overall rate of 36%. Prospective confirmation is warranted.

Not only for melanoma. Subcutaneous pseudoprogression in lung squamous-cell carcinoma treated with nivolumab: A case report.

Rationale: Pseudoprogression, that is, initial tumor growth followed by subsequent tumor regression, has been well described for immunomodulation therapy in melanoma patients. This phenomenon is not well defined in lung cancer. Nivolumab, an anti-PD-1 monoclonal antibody, was recently approved for nonsmall cell lung cancer (NSCLC) as a second-line therapy. Patient concerns and diagnosis: We present a patient with squamous NSCLC, suffering from multiple bone and subcutaneous metastases. Interventions: The patient was treated with nivolumab. Outcomes: A subcutaneous lesion in her upper back grew substantially after the first cycle of nivolumab, and later regressed, with marked improvement in all cancer sites. Lessons: Such pseudoprogression may serve to predict subsequent clinical response.

Durable brain response with pulse-dose crizotinib and ceritinib in ALK-positive non-small cell lung cancer compared with brain radiotherapy

Crizotinib achieves excellent systemic control in anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC); however, central nervous system (CNS) metastases frequently occur as an early event. Whole brain irradiation, the standard treatment, results in neurocognitive impairment. We present a case series of three ALK+ NSCLC patients with progressing CNS metastases who were treated with pulse-dose crizotinib followed by ceritinib. Three ALK+ NSCLC patients treated between 2011 and 2014 (two males, two never smokers, age range 20-54years, all echinoderm microtubule-associated protein-like 4/ALK rearrangement), were diagnosed with progressing cerebral disease while receiving crizotinib. Clinico-pathological characteristics, treatments, and outcomes were analyzed. In two patients the progression was limited to the CNS, and radiological evidence of leptomeningeal spread was present in one patient. Sequential use of crizotinib 500mg administered once daily (pulse-dose) followed by ceritinib on progression achieved control of the disease in the CNS for over 18 months and over 7 months in Patient 1 and Patient 2, respectively. This strategy provided durable CNS control after whole-brain radiotherapy failure in Patient 1, and allowed the whole-brain radiotherapy to be deferred in Patient 2. Limited CNS progression was documented in Patient 3 while he was on standard-dose/pulse-dose crizotinib for 15months; durable (over 7 months) complete remission was achieved with stereotactic radiotherapy and ceritinib. Manipulating the crizotinib schedule in ALK+ NSCLC patients with CNS metastases and using a novel ALK-inhibitor at the time of further progression may provide durable CNS control and allow brain radiotherapy to be deferred.

BRAF Mutant Lung Cancer: Programmed Death Ligand 1 Expression, Tumor Mutational Burden, Microsatellite Instability Status, and Response to Immune Check-Point Inhibitors

Introduction: The efficacy of immune checkpoint inhibitors (ICPi) in BRAF mutant NSCLC is unknown. Methods: Multi‐institutional retrospective chart review identified 39 patients with BRAF mutant NSCLC. The patients were divided into two groups: V600E (group A, n = 21) and non‐V600E (group B, n = 18). Programmed death ligand 1 (PD‐L1) expression, tumor mutational burden (TMB) and microsatellite instability status were assessed in 29 (74%), 11 (28%), and 12 (31%) patients, respectively. Objective response rate, progression‐free survival (PFS) with ICPi, and overall survival were analyzed. Results: High (≥50%), intermediate (1–49%), and no (<1%) PD‐L1 expression was observed in 8 of 19 (42%), 6 of 19 (32%), 5 of 19 (26%), and 5 of 10 (50%), 1 of 10 (10%), and 4 of 10 (40%) cases in groups A and B, respectively. Two tumors in group A showed high TMB (25%); none were microsatellite instability status–high. Twenty‐two patients (group A, n = 12; group B, n = 10) received ICPi. Objective response rate with ICPi was 25% and 33% in groups A and B, respectively (p = 1.0). Median PFS with ICPi was 3.7 months (95% confidence interval [CI]: 1.6–6.6), and 4.1 months (95% CI: 0.1–19.6) in groups A and B, respectively (log‐rank test = 0.81, p = 0.37). Neither BRAF mutation type nor PD‐L1 expression affected the response probability/PFS. Median overall survival was not reached (95% CI: 13–NR) and comprised 21.1 months (95% CI: 1.8–NR) for patients who were and were not exposed to ICPi, respectively (log‐rank test = 5.58, p = 0.018). Conclusions: BRAF mutant NSCLC is associated with high level of PD‐L1 expression, low/intermediate TMB and microsatellite‐stable status. ICPi have favorable activity both in BRAF V600E and BRAF non‐V600E mutant NSCLC.

Effectiveness and safety of nivolumab in advanced non-small cell lung cancer: the real-life data

OBJECTIVES Nivolumab has recently received regulatory approval as a 2nd-line treatment of non-small cell lung cancer (NSCLC). The data regarding its effectiveness and safety in real life setting is lacking. MATERIALS AND METHODS 260 consecutive patients with advanced NSCLC treated with nivolumab at five Israeli cancer centers between January 2015 and March 2016 were evaluated for overall survival (OS) and toxicity. OS was analyzed by the Cox proportional-hazards regression model. Overall response rate (ORR) and progression-free survival (PFS) were assessed in 49 patients using RECIST, v.1.1. RESULTS Median age was 67y (41-99); males 68%; smokers 76%; ECOG PS ≥2 46%; non-squamous/squamous/other/NR 70%/23%/6%/1%; brain metastases 21%; liver metastases 21%; treatment line: 1st/2nd/3rd+-line/NR 6%/64%/26%/4%. With median survival follow-up of 18.5 months (range, 12.0-26.9), 155 (60%) patients died; median OS comprised 5.9 months (95% CI 4.7-7.4). In univariate and multivariate analysis, the only variable which significantly correlated with OS was ECOG PS. Median OS of patients with ECOG PS 0/1 and ECOG PS ≥2 comprised 9.5 months (95% CI, 6.7-NR) and 3.5 months (95% CI, 2.6-4.5), respectively. For 49 patients evaluable for response (median follow-up of 8.4 months (range, 2-16.8), ORR was 35%, median PFS was 2.8 months (95% CI, 1.8-7.7), incidence of pseudo-progression was 9%. The nivolumab safety profile was in accordance with the literature data, except for febrile neutropenia and pericarditis (observed in 1 case each). CONCLUSION In real life setting, the effectiveness of nivolumab is reasonable yet less prominent than it has been demonstrated in clinical trials. ECOG PS ≥2 is associated with poor prognosis.

181P: Anti-PD-1 antibodies in non-small cell lung cancer (NSCLC): The real-life setting experience

patients received anti-PD1 therapy vs 36.1% anti-PDL1 immune checkpoint inhibitors; 41% of patients received immunotherapy agents after two previous chemotherapy lines and 22.9% after 3 or more. With a median follow-up of 24 months (7–90.1), only exor active smokers had response to immunotherapy with an overall rate of 6.6% and disease control rate of 52.5% according to RECIST 1.1. No differences were seen between lines of therapy or immunotherapy strategies, but most of patients (51%) remain on treatment so survival rate were not reached. The most common grade I-II adverse events were fatigue (59%) and anorexia (23%) and pneumonitis grade III was observed in 16.4%. Conclusions: Our data are consistent with recent immunotherapy results showing high disease control rate and durable clinical responses regardless of PDL1 status, PD-1/PDL-1 inhibition or line of therapy used, with manageable toxicity. Legal entity responsible for the study: N/A Funding: N/A Disclosure: All authors have declared no conflicts of interest.

Rare targetable drivers (RTDs) in non-small cell lung cancer (NSCLC): Outcomes with immune check-point inhibitors (ICPi)

OBJECTIVES Efficacy of immune check-point inhibitors (ICPi) in NSCLC with rare targetable drivers (RTDs) is largely unknown. MATERIALS AND METHODS Consecutive patients with NSCLC and RTDs (non-EGFR/ALK, n-82) were selected from the Davidoff Cancer Center database. ORR, PFS, OS with ICPi, OS since advanced disease diagnosis, TMB, MSI, and PD-L1 expression were analyzed; uni- and multivariate PFS and OS analyses were done. OS with ICPi was compared between the RTD cohort and the non-selected NSCLC cohort (n-278). RESULTS Of 50 tumors tested, 32%, 38%, and 30% were associated with ≥50%, 1-49% and <1% PD-L1 expression, respectively. Median TMB (n-48) comprised 4 muts/Mb (0-57); TMB ≥ 10 muts/Mb was seen in 19% of tumors. Both TMB and PD-L1 expression varied across different RTDs. All the 47 tumors were MSI stable. ORR with ICPi (n-44) was 16%, median PFS was 3.2 months (95% CI, 2.6-5.0), median OS was 16.2 months (95% CI, 8.4-NR). No correlation was seen between OS with ICPi and PD-L1 expression (p > 0.4), TMB (p > 0.8), or RTD type (p > 0.3). In the multivariate analysis, ECOG PS (p-0.005), targeted agents exposure (p-0.005), and ICPi exposure (p-0.04) were the only variables which correlated with OS since advanced disease diagnosis. Median OS since advanced disease diagnosis comprised 32 months (95% CI, 19.9-44.9) and 13 months (95% CI, 6.6-15.9) for patients who were and were not exposed to ICPi, respectively (log-rank test-6.3; p-0.01). In the inter-cohort comparison, for patients matched for ECOG PS (0/1), median OS with ICPi comprised 17.5 months (95% CI, 8.1-NR) and 8.6 months (95% CI, 6.7-NR) for RTD and non-selected patients, respectively (log-rank test-2.4, p-0.1). CONCLUSION In NSCLC with RTD, ICPi have favorable efficacy and independent impact on OS. NSCLC with RTD is associated with MSI stable status and variable levels of PD-L1 expression and TMB; their predictive value remains to be determined.