Background: There are scarce data on venous thromboembolism (VTE) rates among non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors (ICI). The Khorana Score (KS), used to guide thromboprophylaxis in cancer patients, was validated in patients receiving chemotherapy.Objective: To assess VTE rates and KS performance among NSCLC patients treated with ICI or chemotherapy. Methods:We performed a retrospective cohort study of NSCLC patients starting either ICI or platinum-based chemotherapy. The 6-month cumulative incidence of VTE in the ICI and chemotherapy cohorts and hazard ratios (HR) with 95% confidence intervals (CI) were calculated, using death as a competing risk. Subgroup analysis of low (0-1) and high (≥2) KS risk groups was performed. Results:The study included 345 NSCLC patients receiving single agent ICI (n = 176) or chemotherapy (n = 169). The 6-month cumulative incidence of VTE was 7.1% in the chemotherapy cohort and 4.5% in the ICI cohort (HR for chemotherapy = 1.6, 95% CI 0.66-3.9). Among chemotherapy treated patients, the high-risk KS group had a trend toward a higher VTE incidence, compared with patients with a low-risk KS (HR 3.04, 95% CI 0.82-11.22). Among ICI-treated patients, the high-risk KS group had a trend toward a lower VTE incidence compared with the low-risk group (HR 0.17, 95% CI 0.02-1.36). Conclusions: VTE rates were higher among NSCLC patients treated with platinumbased chemotherapy than those treated with ICI alone, though the precision of the relative estimate is low. The KS did not identify high-risk ICI-treated patients, suggesting that an ICI-specific risk model is warranted.

The JAK2V617F mutation has emerged in recent years as a diagnostic as well as treatment target in patients with polycythemia vera (PV). We analyzed JAK2V617F allele burden (JAK2(V617F)) in a Jewish population with PV. Results were correlated with disease symptoms and complications. Median JAK2(V617F) was 48% and 54% in patients of Ashkenazi and non-Ashkenazi origin, respectively (p =0.75). Higher JAK2(V617F) was seen in patients with imaging-proven splenomegaly (p =0.01). A correlation between JAK2(V617F) and the weekly hydoxyurea dose needed for disease control was found (p =0.043). In addition, a trend for higher allele burden in patients with longer disease duration (p =0.064) and those treated with cytoreductive drugs other than hydroxyurea (p =0.056) was noted. Higher JAK2(V617F) was seen in patients with transformation to myelofibosis (p =0.0001), but not in patients with vascular complications. JAK2(V617F) may assist in prognostic stratification of patients with PV.

<b><i>Introduction:</i></b> Immune checkpoint inhibitors (ICI) are the new standard therapy in patients with metastatic NSCLC (mNSCLC). Metformin, previously associated with improved chemotherapy efficacy in diabetic and nondiabetic cancer patients, was recently associated with increased ICI efficacy. In this study, we aimed to explore the correlations between diabetes mellitus (DM), metformin use, and benefit from ICI in mNSCLC patients. <b><i>Methods:</i></b> All mNSCLC patients treated with ICI in our center between February 2015 and April 2018 were identified. Demographic and clinical data were extracted retrospectively. Cox proportional hazards regression, <i>t</i> tests, and χ² tests were employed to evaluate associations of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR), with DM status, metformin use, and HbA1c levels, as appropriate. <b><i>Results:</i></b> Of 249 mNSCLC patients treated with ICI, 57 (22.8%) had DM. Thirty-seven (64.9% of all diabetic patients) patients were treated with metformin. A significant negative correlation of DM with PFS and OS was demonstrated (HR 1.5 [1.01–2.06], <i>p</i> = 0.011, and HR 1.5 [1.08–2.08], <i>p</i> = 0.017, respectively). Metformin exposure had no significant correlation with PFS or OS in diabetic mNSCLC patients (HR 1.08 [0.61–1.93], <i>p</i> = 0.79, and HR 1.29 [0.69–2.39], <i>p</i> = 0.42, respectively). There were no differences between groups with respect to ORR and DCR. <b><i>Conclusion:</i></b> Our data show a potential negative relationship between DM and ICI efficacy in mNSCLC patients. In contrast to reports with chemotherapy, we found no positive relationship between metformin use and ICI therapy in diabetic patients with mNSCLC. Further studies are needed to evaluate the effect of metformin in nondiabetic mNSCLC patients.

The standard of care for stage III non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by durvalumab. Although doses higher than 66 Gy are standard in our center, they were used in only 6.9% of patients in the PACIFIC trial. We report our experience with durvalumab after high-dose radiotherapy. The database of a tertiary hospital for patients with stage III NSCLC who were treated with CRT and adjuvant durvalumab was evaluated. Progression-free survival (PFS), overall survival (OS), and local-regional failure (LRF) were measured from the administration of durvalumab. Thirty-nine patients were included. All were treated with intensity-modulated radiation (mean dose 69.9 Gy); Median follow-up time was 20.4 months (range 1–35.4). At 12 months, PFS was 49%, OS 79%, and LRF 14%. Intrathoracic failure at first progression was demonstrated in 8 (21%) patients. Adverse events requiring corticosteroids occurred in 10(25.6%) patients: pneumonitis – 6 (15.4%), hepatitis – 2 (5.1%), and arthralgia and pericarditis – 1 (2.6%). One patient (2.6%) died of pneumonitis. The occurrence of pneumonitis was significantly associated with lung V5 (55% vs. 42%, p = .04) and V20 (28% vs. 19%, p = .01) and mean lung dose (14.8 Gy vs.11.6 Gy, p = .05). The similar 12-month PFS and OS rates of our cohort and the PACIFIC trial support the use of high-dose radiotherapy in patients with stage III NSCLC. Treatment-related mortality was similar to the PACIFIC results. The intrathoracic failure rate in our cohort was lower than that reported from the PACIFIC trial, suggesting that radiation dose escalation may improve local control.

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Background: Tropomyosin receptor kinase (TRK fusions) involving the genes NTRK1, NTRK2, and NTRK3 occur in a broad range of malignancies including breast cancers (BC) with secretory features. Larotrectinib, the first selective TRK inhibitor in clinical development, has demonstrated an overall response rate of 75% by independent radiology review across various solid tumors, with a favorable safety profile. Here we report on a case series of TRK fusion BC patients treated with larotrectinib alone or in combination. Methods: Patients were treated with oral larotrectinib in the NAVIGATE global phase II study or in single-patient compassionate-use protocols. All patients received the Phase 2 dose of 100mg BID on a continuous 28d schedule. Efficacy was evaluated using RECIST v1.1. Results: As of June 2018, 5 TRK fusion BC patients had been treated, all with secretory characteristics, but diverse ER/PR/HER2 positivity (Table); 2 patients were triple negative. Four patients harbored ETV6-NTRK3 fusions. Larotrectinib treatment yielded a response rate of 80% (4/5 PRs). All responses occurred within the first 2 cycles of therapy and cancer-related symptoms resolved rapidly. No treatment-related Grade ≥3 adverse events have been reported. Patient 2 (14 yr) presented with a recurrent fungating mass (10.4x8.5 cm) having failed multiple rounds of chemotherapy. Significant reduction in tumor size was noted after one week of larotrectinib treatment with near complete resolution after 2 months.1 Patient 3 (37 yr) had extensive involvement of the lung and pleura, bilateral pleural effusions, peritoneal infiltration with ascites, severe dyspnea with PS=3. There was rapid improvement with larotrectinib treatment and the patient was PS=1 after 2 weeks. At 6 weeks, there was &gt;80% reduction in tumor size.2 Patient 5 had a synchronous, locally advanced TRK fusion positive, ER+/HER2- secretory BC and TRK fusion negative, ER+/HER2- metastatic lobular BC. Prior to TRK inhibition, this patient received 2-months of palbociclib/letrozole to which the TRKfusion negative lobular cancer responded, while the TRK fusion SBC did not. The patient tolerated the larotrectinib/letrozole combination with no notable toxicities and experienced a PR in both sites, now ongoing for 11 months. Conclusions: We provide the first evidence that larotrectinib is effective in the treatment of BC harboring NTRK gene fusions. Assays capable of identifying NTRK gene fusions should be considered when profiling patients with BC, especially for patients with secretory BC. Table:Subject summarySubject IDSubtypeRegimenNTRK gene fusionER/PR/HER2 statusBest ResponseProtocol1Invasive ductal carcinoma (NOS)larotrectinibTPM3-NTRK1ER+/PR+/HER2-PDNAVIGATE Ph II2SecretorylarotrectinibETV6-NTRK3ER-/PR-/HER2-PRCompassionate use3Invasive ductal with secretory featureslarotrectinibETV6-NTRK3ER-/PR-/HER2-PRCompassionate use4Invasive ductal with secretory featureslarotrectinibETV6-NTRK3ER+/PR+/HER2+PRCompassionate use5*Secretorylarotrectinib + letrozoleETV6-NTRK3ER+/PR-/HER2-PRCompassionate use*- synchronous TRK fusion negative invasive lobular 1. Shukla et al., JCO Precis Oncol 2017, epub 2. Landman et al., Clin Breast Cancer, 2018, 18:e267-e270. Citation Format: Meric-Bernstam F, Shukla N, Peled N, Landman Y, Onitilo A, Montez S, Ku NC, Hyman DM, Drilon A, Hong DS. Activity of larotrectinib, a highly selective inhibitor of tropomyosin receptor kinase, in TRK fusion breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-02.

Background Our previous study of pulmonary function in 34 patients with early breast cancer without preexisting lung disease showed that anthracycline- and taxane-based adjuvant dose-dense chemotherapy (DDC) caused a significant 16.4% mean reduction in carbon monoxide diffusing capacity (DLCO). The present study reports the pulmonary and oncological outcomes of these patients on long-term follow-up. Patients and methods The primary endpoint was DLCO measured by the pulmonary function test (PFT) performed at a median of 27 months after DDC (range, 8–97) in 25 patients without disease recurrence. DLCO values were recorded as a percentage of predicted values according to age, height, and hemoglobin level and analyzed relative to baseline pre-DDC DLCO values. The secondary endpoints were symptoms, additional therapies, and cancer outcomes during a median of 11 years' follow-up (range, 4.4–11.4). Results A longitudinal general linear model showed significant effects of time on DLCO and its trend (F(1, 87) = 14.68, p < 0.001 and F(1, 87) = 10.26, p=0.002, respectively). Complementary descriptive analysis showed a significant recovery on the follow-up PFT (75.6% vs. 81.9%, p=0.002), but it was still significantly lower than the baseline DLCO (81.9% vs. 92.0%, p=0.003). Five patients (20%) still showed a >20% relative DLCO reduction from baseline. Patients with dyspnea or fatigue at later clinical follow-up had a significantly lower DLCO value on the follow-up PFT than nonsymptomatic patients (80.5% vs. 92.1%, p=0.02). DLCO recovery was inversely correlated with age (R = −0.39, p=0.05), but no significant correlation was found with the length of time until the follow-up PFT or additional therapies. There was no association of DDC-related DLCO reduction with cancer outcomes. Conclusions The significant reduction in DLCO seen after DDC in patients with potentially curable breast cancer is evident years afterwards, especially in older patients. While most patients partly recover, some will have a lasting symptomatic DLCO impairment.

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