The Relationship of Diabetes Mellitus to Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: 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. METHODS: 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, t 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. RESULTS: 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], p = 0.011, and HR 1.5 [1.08-2.08], p = 0.017, respectively). Metformin exposure had no significant correlation with PFS or OS in diabetic mNSCLC patients (HR 1.08 [0.61-1.93], p = 0.79, and HR 1.29 [0.69-2.39], p = 0.42, respectively). There were no differences between groups with respect to ORR and DCR. CONCLUSION: 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.

Stereotactic Radiosurgery for Brain Metastases in Small Cell Lung Cancer: The Davidoff Cancer Center Experience.

BACKGROUND: Prophylactic cranial irradiation (PCI) exclusion in favor of brain magnetic resonance imaging (MRI) staging and surveillance in the management of small cell lung cancer (SCLC) is controversial yet accepted by some centers. The use of MRI suggests performing stereotactic radiosurgery (SRS) treatment for limited brain metastases. Data regarding SRS efficacy in this setting is limited. OBJECTIVES: To assess intracranial objective response rate (iORR), progression-free survival (iPFS), intracranial failure patterns, overall survival (OS) and time-to-whole-brain radiation therapy (WBRT)/death, whichever occurred first (TTWD) with SRS in SCLC. METHODS: The study comprised 10 consecutive SCLC patients with brain metastases treated with SRS and followed-up at Davidoff Cancer center between Aug 2012 and March 2019. Brain MRI images were reviewed by a neuro-radiology specialist. RESULTS: iORR was 57% as assessed by response assessment in neuro-oncology brain metastases. Intracranial progression developed in 8 patients. Median iPFS was 4.0 months (95% confidence interval [95%CI] 1.7-7.2). In-site, off-site and combined pattern of intracranial failure was seen in 0, 5, and 3 patients, respectively; median number of new brain lesions following SRS was 4 (range, 1-12). SRS was performed 10 additional times in 6 patients (median number of lesions irradiated per round was 1, range 1-5). WBRT was administered in 3 patients. Median TTWD was 20.9 months (95% CI, 1.9-26.8). Median OS since SRS administration was 23.2 months (95% CI, 4.2-not reached). CONCLUSIONS: MRI surveillance with multiple rounds of SRS may serve a reasonable alternative to PCI or therapeutic WBRT in SCLC.

First-line programmed death-1 inhibitor treatment for locoregionally advanced or metastatic cutaneous squamous cell carcinoma - A real-world experience from Israel.

Objective: Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide. It is usually treated surgically, with very high cure rates. However, in 3%-7% of cases, cSCC metastasizes to lymph nodes or distant organs. Many of the affected patients are elderly with comorbidities who are not candidates for standard-of-care curative-intent treatment with surgery and/or radio-/chemotherapy. Immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) pathways, have recently emerged as a potent therapeutic option. The present report presents the Israeli experience with PD-1 inhibitors for the treatment of loco-regionally advanced or metastatic cSCC in a diverse and elderly population, with or without the addition of radiotherapy. Material and methods: The databases of two university medical centers were retrospectively searched for patients with cSCC treated with the PD-1 inhibitors cemiplimab or pembrolizumab between January 2019 and May 2022. Data on baseline, disease-related, treatment-related, and outcome parameters were collected and analyzed. Results: The cohort included 102 patients of a median age 78.5 years. Evaluable response data were available for 93. The overall response rate was 80.6%: complete response in 42 patients (45.2%) and partial response in 33 (35.5%). Stable disease was recorded in 7 (7.5%) and progressive disease in 11 (11.8%). Median progression-free survival was 29.5 months. Radiotherapy was administered to the target lesion during PD-1 treatment in 22.5% of patients. mPFS was not significantly different in patients who treated with RT than patients how did not (NR vs 18.4 months, HR=0.93, 95%CI: 0.39 - 2.17, p<0.859). Any-grade toxicity was recorded in 57 patients (55%), including grade _3 in 25, of whom 5 (5% of cohort) died. Compared to toxicity-free patients, patients with drug toxicity had better progression-free survival (18.4 months vs not reached, HR=0.33, 95% CI: 0.13-0.82, p=0.012) and higher overall response rate (87% vs 71.8%, p=0.06). Conclusion: This retrospective real-world study showed that PD-1 inhibitors were effective in the treatment of locally advanced or metastatic cSCC and appeared to be amenable for use in elderly or fragile patients with comorbidities. However, the high toxicity warrants consideration against other modalities. Induction or consolidation radiotherapy may improve the results. These findings need to be corroborated in a prospective trial.

Next-generation sequencing in thyroid cancers: do targetable alterations lead to a therapeutic advantage?: A multicenter experience.

ABSTRACT: Radioiodine-refractory thyroid cancers (IRTCs) are uncommon and have a poor prognosis. Treatment options for radioiodine-refractory and anaplastic tumors (ATCs) are limited. Although the genomic landscape of thyroid cancer has been studied, there is little evidence on whether next-generation sequencing (NGS) findings translate to tumor control.We analyzed all patients with IRTC and ATC who underwent commercially available NGS in 3 cancer centers.Twenty-two patients were identified, 16 patients with IRTCs and 6 patients with ATCs. Eighteen (82%) had targetable findings in NGS, nine patients were treated accordingly. Median progression-free survival for targeted treatment was 50 months [95% confidence interval (CI95%) 9.8-66.6] and2 months (CI95% 0.2-16.5) for IRTC and ATC, respectively. Of 4 patients who achieved durable responses of 7 to 50 months, 2 are ongoing. The estimated median OS of IRTC receiving targeted treatment was not reached (CI95% 89.7-111.4 months) and was 77.8 months (CI95% 52.5-114.6) for patients treated conventionally (P = .3).NGS may detect clinically significant genetic alterations and benefit patients with advanced thyroid cancers.

Immune-related Neutropenia Following Treatment With Immune Checkpoint Inhibitors.

The existing data with regard to immune-related neutropenia (irN), a rare (incidence-1%) immune-related adverse event of immune checkpoint inhibitors, are scarce. Eight patients with irN were identified through internal databases of 3 participating Israeli cancer centers. In addition, 11 original articles focusing on the clinical course of 24 patients with irN were selected during the PubMed search. Descriptive analysis of clinical and pathologic factors related to irN was performed (n=32); the effect of these on the irN outcomes was assessed. An algorithm for irN evaluation and treatment was proposed. The median time-to-onset of irN (n=32) was 60 days (range, 10-465 d). Grade 3-5 irN, febrile neutropenia, and irN-related death occurred in 81%, 50%, and 9% of patients, respectively. In all, 56%, 22%, 62%, and 25% of patients received PO corticosteroids, IV corticosteroids, granulocyte colony-stimulating factor (GCSF), and intravenous immunoglobulins (IVIG), respectively, with an improvement/resolution rate of 84%. Odds ratios for irN improvement/resolution were as follows: 1.40 [95% confidence interval (CI), 0.03-68.72], 0.43 (95% CI, 0.04-4.22), 2.60 (95% CI, 0.07-97.24), 0.36 (95% CI, 0.03-4.38), 4.02 (95% CI, 0.16-99.48), 2.01 (95% CI, 0.32-12.70), 1.08 (95% CI, 0.02-49.89), 0.42 (95% CI, 0.06-2.91), and 2.73 (95% CI, 0.42-17.51) for granulocyte hyperplasia, granulocyte/all lineage hypoplasia, granulocyte maturation blockade, lymphocyte infiltration on bone marrow biopsy, IV corticosteroids, PO corticosteroids, cyclosporine, IVIG, and GCSF, respectively (P>0.05 for all factors). IrN recurrence rate following immune checkpoint inhibitors rechallenge was 80%. IrN is a rare, life-threatening, early-onset immune-related adverse event. Differentiating between the central, peripheral, and modified peripheral types allows a better prognosis definition. Corticosteroids and GCSF represent the main treatment approaches; IVIG and cyclosporine should be used as salvage treatment.

Tyrosine Kinase Inhibitors as a Treatment of Symptomatic CNS Metastases in Oncogene-Driven NSCLC.

Central nervous system (CNS) metastases occur frequently in oncogene-driven non-small cell lung cancer (NSCLC). Standard treatment approaches can potentially delay systemic treatment (surgical intervention) or result in neurocognitive impairment (radiotherapy). Recently, next-generation tyrosine kinase inhibitors (TKIs) have demonstrated remarkable intracranial activity. However, most clinical trials did not enroll patients suffering neurological symptoms. Our study aimed to assess the CNS activity of targeted therapies in this patient population. We present a case series of nine NSCLC patients with either EGFR mutation or ALK rearrangement and symptomatic CNS metastases that were treated with TKIs. Clinicopathological characteristics, treatment, and outcomes were analyzed. Most patients presented with symptomatic CNS metastases at time of metastatic disease presentation (6/9). Additionally, the majority of patients had leptomeningeal disease (6/9) and multiple parenchymal metastases. Patients presented with a variety of CNS symptoms with the most common being nausea, vomiting, headache, and confusion. Most patients (6/9) responded rapidly both clinically and radiographically to the targeted treatment, with a marked correlation between systemic and intracranial radiographic response. In conclusion, upfront use of next-generation TKIs in patients with oncogene-driven NSCLC with symptomatic CNS metastases is associated with reasonable intracranial activity and represents a valuable treatment option.