Driver mutation characteristics of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in advanced non-small cell lung cancer.

OBJECTIVES: The identification and targeting of actionable genomic alterations (AGA) have revolutionized the treatment of cancer in general and mostly for non-small cell lung cancer (NSCLC). We investigated whether in NSCLC patients PIK3CA mutations are actionable. MATERIALS AND METHODS: Chart review was performed of advanced NSCLC patients. PIK3CA mutated patients were analyzed as two groups: Group A: without any non-PIK3CA established AGA; Group B: with coexisting AGA. Group A was compared to a cohort of non-PIK3CA patients (group C), using t-test and chi-square. To evaluate the impact of PIK3CA mutation on outcome, we compared Group A survival to age/sex/histology matched cohort of non-PIK3CA mutated patients (group D) by Kaplan-Meier method. A patient with a PIK3CA mutation was treated with a PI3Ka-isoform selective inhibitor BYL719 (Alpelisib). RESULTS: Of a cohort of 1377 patients, 57 are PIK3CA mutated (4.1%). Group A: n-22, group B: n-35. Group A median age is 76 years, 16 (72.7%) men, 10 (45.5%) squamous, 4 (18.2%) never smokers. Two never-smoker female adenocarcinoma patients had solitary PIK3CA mutation. One of them was treated with a PI3Ka-isoform selective inhibitor BYL719 (Alpelisib), with rapid clinical and partial radiological improvement. Group B, compared with Group A, included younger patients (p = 0.030), more females (p = 0.028) and more adenocarcinoma cases (p < 0.001). Compared to group C, group A patients were older (p = 0.030) and had more squamous histology (p = 0.011). CONCLUSION: In a small minority of NSCLC patients with PIK3CA mutation there are no additional AGA. PIK3CA mutations may be actionable in these cases.

Chemoradiation followed by adjuvant durvalumab in stage III non-small cell lung cancer: Real-world comparison of treatment outcomes to historical controls treated with chemoradiation alone.

OBJECTIVE: Compare outcomes in patients with stage III non-small cell lung cancer (NSCLC) treated with chemoradiation and adjuvant durvalumab to historical controls treated with chemoradiation alone. METHODS: The records of patients with stage III NSCLC treated with definitive chemoradiation ± adjuvant durvalumab were reviewed retrospectively. Primary endpoints were progression free survival (PFS), overall survival (OS), and adverse events (AE). RESULTS: Between September 2009 and September 2020, 215 patients were treated with concurrent chemoradiation (n = 144) or concurrent chemoradiation followed by adjuvant durvalumab (n = 71). Compared to historical controls, durvalumab use was associated with improved PFS: median (27 months vs. 10 months, p < 0.0001), 1-year (83.1% vs. 43.8, p < 0.0001); and improved OS; median (not reached vs. 24 months, p < 0.0001), 1-year (85.9% vs. 81.9%, p < 0.0001). Multivariate analysis showed adjuvant durvalumab was associated with increased OS (p = 0.005) and PFS (p = 0.001). Within the durvalumab group, only clinical stage IIIA versus IIIB/C was associated with improved OS (p = 0.049), but not PFS. There was no association between PFS or OS and Eastern Cooperative Oncology Group (ECOG) score, prior history of immune disease, programmed death-ligand 1 (PD-L1) receptor status, delay in starting durvalumab beyond 42 days, or development of an AE. During durvalumab treatment, 63 AE were reported in 52 patients with treatment discontinuation in 11. Pneumonitis was the most common AE reported (n = 35, 49%). Most AE were grade 1-2 (n = 57). Grade 3-4 AE were uncommon (n = 6) and none were grade 5. CONCLUSION: Treatment with adjuvant durvalumab following chemoradiation was associated with improved PFS and OS compared to chemoradiation alone.

Nivolumab in Non-Small Cell Lung Cancer: Real World Long-Term Survival Results and Blood-Based Efficacy Biomarkers.

OBJECTIVES: We aimed to examine clinical data and baseline blood test results as potential predictive biomarkers for benefit from nivolumab, in advanced non-small cell lung cancer patients (NSCLC). MATERIALS AND METHODS: A chart review was performed of 108 advanced NSCLC patients who commenced treatment with nivolumab between 2015-6 at three Israeli cancer centers, and for whom laboratory tests results were available. Data collected included sex, age, ECOG-PS, histology and number of previous lines of treatment. Baseline blood test results collected: absolute lymphocyte and neutrophil count (ANC), white blood cells (WBC), hemoglobin, platelets, albumin and lactate dehydrogenase (LDH). Neutrophil to Lymphocyte Ratio and 'derived NLR' (dNLR = (ANC/[WBC-ANC])) were calculated. Disease control at six months (DC6) was defined as any tumor shrinkage or stable disease during the first six months of nivolumab treatment. The association between clinical/laboratory variables and survival was tested with a Cox proportional hazard model. Data cut-off occurred in November 2019. RESULTS: 35 patients (32.4%) achieved DC6. Median overall survival (OS) of entire study population was 5.4 months. Four year survival rate was 16%. Achievement of DC6 strongly correlated with longer OS (HR 0.12, 95% C.I. 0.07-0.21, p<0.001). In univariate and multivariate analysis, dNLR, albumin and LDH correlated significantly with OS. No variables correlated significantly with DC6 in multivariate analysis. Based on albumin and LDH, we produced a score called CLAS (combined LDH and albumin score), including four prognostic groups of patients. Patients having low albumin and high LDH had the worst prognosis. CONCLUSION: In real-life setting, long-term efficacy of nivolumab in advanced line treatment of NSCLC is consistent with clinical trials. Response or stability of disease during first six months of treatment is associated with prolonged survival. We propose a novel score (CLAS) that may be useful for predicting outcome in nivolumab-treated NSCLC patients, but further validation is required.

Real-World Analysis of the Impact of Radiotherapy on Immunotherapy Efficacy in Non-Small Cell Lung Cancer.

BACKGROUND: Immunotherapy (IO) provides a significant benefit for a subgroup of non-small cell lung cancer (NSCLC) patients. Radiotherapy (XRT) might enhance the efficacy of IO. We evaluated the impact of the specifics of XRT treatments on the OS of IO-treated NSCLC patients. METHODS: Metastatic NSCLC patients treated with IO were retrospectively identified. Parameters included demographics, tumor characteristics, IO and XRT details. Correlation between the parameters and OS was tested with Cox regression. RESULTS: 453 patients were included. No XRT was given to 167 (36.9%) patients, whereas XRT prior and after IO had 182 (40.2%) and 104 (22.9%) patients, respectively. XRT total doses between 30 and 40 Gy had better overall survival (OS) compared to non-irradiated patients (hazard ratio (HR) 0.5, 95% CI 0.25-1.0, p = 0.049). Worse outcome was seen with total doses ≤ 10 Gy (HR 1.67, 95% 1.13-2.5, p = 0.01), XRT fractions of 4.1-8 Gy (HR 1.48, 95% CI 1.05-2.1, p = 0.027) and XRT to the bone (HR 1.36, 95% CI 1.01-1.8, p = 0.04). Several clinical parameters correlated with OS in the univariate analysis of the IO-treated patients. While, in the multivariate analysis, only ECOG-PS, treatment line, type of IO, albumin and NLR remained statistically significant. CONCLUSION: Specific doses, fractions and sites of XRT correlated with the OS of IO-treated NSCLC patients in the univariate analysis, although not in the multivariate analysis.

BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors.

OBJECTIVES: Little is known regarding the outcomes of systemic treatments in BAP1-altered malignant pleural mesothelioma (MPM). MATERIALS AND METHODS: Forty five patients with MPM [group A: eight MPM patients with BAP1 inactivating mutation/copy number loss (FoundationOne® CDx/TEMPUSxT), selected from the electronic databases of four Israeli cancer centers (ICC); group B: 37 consecutive (years 2016-2018) MPM patients selected from the electronic databases of two ICC-of those six patients without a BAP1 alteration (group B1) and 31 patients not tested for BAP1 (group B2)] were analyzed for ORR, PFS (mRECIST), and OS with 1st-line platinum/pemetrexed+/-antiangiogenic drug (CT, n-28), immune check-point inhibitors (ICPi, n-16) and poly (ADP-ribose) polymerase inhibitors (PARPi, n-4). OS since diagnosis (OSDx) was assessed. RESULTS: There were no differences in ORR or mPFS with CT between the groups: ORR-50% vs. 47% vs. 50% vs. 47% (p>0.9), mPFS-9.1mo (95% CI, 1.2-16.1) vs. 9.2mo (95% CI, 2.9-13.3) vs. 7.2mo (95% CI, 2.3-NR) vs. 10.9mo (95% CI, 2.9-20.3) (p>0.8) in groups A, B, B1, and B2, respectively. There were no differences in ORR or mPFS with ICPi between the groups: ORR-0% vs. 27% vs. 33% vs. 25% (p>0.2), mPFS-2.5mo (95% CI, 1.4-3.7) vs. 3.0mo (95% CI, 1.3-10.5) vs. 2.0mo (95% CI, 1.9-NR) vs. 4.5mo (95% CI, 0.3-10.5) (p>0.3) in groups A, B, B1, and B2, respectively. In group A, no responses were seen with PARPi; mPFS with PARPi was 1.8mo (95% CI, 1.8-NR). OSDx was 98.3mo (95% CI, 9.7-98.3) vs. 19.4mo (95% CI, 9.7-47.3) vs. 18.8mo (95% CI, 8.5-NR) vs. 19.5mo (95% CI, 8.3-82.2) in groups A, B, B1, and B2, respectively (p>0.3). CONCLUSIONS: BAP1-altered MPM, as compared to non-selected MPM, is characterized by similar efficacy of CT and ICPi. Numerically longer OS in BAP1-altered MPM may reflect favorable tumor biology. No responses were observed with PARPi.

Real-world survival outcomes with immune checkpoint inhibitors in large-cell neuroendocrine tumors of lung.

BACKGROUND: Little is known regarding the efficacy of immune checkpoint inhibitors (ICI) in patients with advanced large-cell neuroendocrine lung carcinoma (aLCNEC). METHODS: 125 consecutive patients with aLCNEC were identified in the electronic databases of 4 participating cancer centers. The patients were divided into group A (patients who received ICI, n=41) and group B (patients who did not receive ICI, n=84). Overall survival since advanced disease diagnosis (OS DX) and OS since ICI initiation (OS ICI) were captured. RESULTS: With a median follow-up of 11.8 months (mo) (IQR 7.5-17.9) and 6.0mo (IQR 3.1-10.9), 66% and 76% of patients died in groups A and B, respectively. Median OS DX was 12.4mo (95% CI 10.7 to 23.4) and 6.0mo (95% CI 4.7 to 9.4) in groups A and B, respectively (log-rank test, p=0.02). For ICI administration, HR for OS DX was 0.59 (95% CI 0.38 to 0.93, p=0.02-unadjusted), and 0.58 (95% CI 0.34 to 0.98, p=0.04-adjusted for age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), presence of liver metastases and chemotherapy administration). In a propensity score matching analysis (n=74; 37 patients in each group matched for age and ECOG PS), median OS DX was 12.5 mo (95% CI 10.6 to 25.2) and 8.4 mo (95% CI 5.4 to 16.9) in matched groups A and B, respectively (log-rank test, p=0.046). OS ICI for patients receiving ICI as monotherapy (n=36) was 11.0 mo (95% CI 6.1 to 19.4). CONCLUSIONS: With the limitations of retrospective design and small sample size, the results of this real-world cohort analysis suggest a positive impact of ICI on OS in aLCNEC.

Immunotherapy response modeling by ex-vivo organ culture for lung cancer.

One of the major hurdles for the advancement of cancer immunotherapy is lack of robust, accessible experimental models. We aimed to produce an ex-vivo organ culture (EVOC) model of immunotherapy for non-small cell lung cancer (NSCLC). Freshly resected early stage tumors were collected from the operating room, fragmented to clusters < 450 µm and cultured with fetal calf serum and human autologous serum. The resulting EVOC includes cancer epithelial cells within tumor tissue clusters and immune cells. Original tissue features are reflected in the EVOCs. The response to immune checkpoint inhibitors (ICI) was assessed by IFNγ gene induction. Interestingly, IFNγ EVOC induction was numerically higher when anti-CTLA4 was added to anti-PD-L1 treatment, supporting the notion that anti-CTLA4 impacts cancer partly through tumor-resident immune cells. In parallel, immunohistochemistry (IHC) for key immune-related proteins was performed on the formalin-fixed paraffin embedded (FFPE) corresponding tumors. EVOC IFNγ induction by ICI correlated with basal non-induced IFNγ, CD8, CD4 and FOXP3 mRNA levels within EVOCs and with tumor-FFPE-IHC for CD8 and granzyme B. A weaker correlation was seen with tumor-FFPE-IHC for CD3, CD4, CD68, FOXP3 and tumor-PD-L1. Tertiary lymphoid structure density was also correlated with the ICI response. Our study provides novel data about biomarkers that correlate with ICI-induced response of early stage NSCLC. Retention of the microenvironment and minimal addition of exogenous factors suggest this model to reliably represent the original tumor. The cluster-based EVOC model we describe can provide a valuable, yet simple and widely applicable tool for the study of immunotherapy in NSCLC.

Alternative nivolumab duration and scheduling in advanced nonsmall cell lung cancer: A real-world evidence.

In advanced nonsmall cell lung cancer (aNSCLC), stopping nivolumab after 12 months negatively affects outcomes. We performed a world data-based analysis assessing the value of nivolumab continuation and optimal dosing beyond 24 months. Out of 697 consecutive patients with aNSCLC in whom nivolumab was initiated between 2015 and 2018, 45 patients receiving nivolumab for ≥24 months were selected. These were divided into Groups A: nivolumab administered at a dose 3 mg/kg q2 weeks/240 mg q2 weeks/480 mg q4 weeks, n = 25; B: nivolumab re-scheduled to a nonstandard dose 3 mg/kg q3 weeks-q8 weeks, n = 13; C: nivolumab stopped after 24 months, n = 7; (in Groups B and C-for reasons other than progressive disease or intolerable toxicity). Progression-free survival (PFS) (Revised Response Evaluation Criteria in Solid Tumors, version 1.1) and safety (Common Terminology Criteria for Adverse Events, version 4.03) were assessed. With median follow-up of 35.6 months (interquartile range 28.4-41.8), 4%, 31%, 29% and 30% of patients progressed in Groups A, B, C and B+C, respectively. PFS at 36 months since nivolumab initiation comprised 100%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. PFS at 40 months since nivolumab initiation comprised 83%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. Allocation to Group A vs Group B, C and B+C was associated with hazard ratio for PFS-0.20 (95% confidence interval [CI], 0.02-1.77, P-.15), 0.20 (95% CI, 0.02-2.25, P-.19) and 0.20 (95% CI, 0.02-1.66, P-.14), respectively. No differences in newly occurring or worsening adverse events between the groups were observed. A trend for worse PFS was observed with alternative nivolumab scheduling or quitting 24 months after initiation. Continuing nivolumab at a standard dose until disease progression or intolerable toxicity remains the standard treatment option.

Predicting brain metastasis in early stage non-small cell lung cancer patients by gene expression profiling.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-death due to early metastatic spread, in many cases primarily to the brain. Organ-specific pattern of spread of disease might be driven by the activity of a specific signaling pathway within the primary tumors. We aimed to identify an expression signature of genes and the relevant signaling associated with the development of brain metastasis (BM) after surgical resection of NSCLC. METHODS: Rapidly frozen NSCLC surgical specimens were procured from tumor banks. RNA was extracted and analyzed by RNA-sequencing (Illumina HiSeq 2500). Clinical parameters and gene expression were examined for differentiating between patients with BM, patients with metastases to sites other than brain, and patients who did not develop metastatic disease at a clinically significant follow up. Principal component analysis and pathway enrichments studies were done. RESULTS: A total of 91 patients were included in this study, 32 of which developed BM. Stage of disease at diagnosis (P=0.004) and level of differentiation (P=0.007) were significantly different between BM and control group. We identified a set of 22 genes which correlated specifically with BM, and not with metastasis to other sites. This set achieved 93.4% accuracy (95% CI: 86.2-97.5%), 96.6% specificity and 87.5% sensitivity of correctly identifying BM patients in a leave-one-out internal validation analysis. The oxidative phosphorylation pathway was strongly correlated with BM risk. CONCLUSIONS: Expression level of a small set of genes from primary tumors was found to predict BM development, distinctly from metastasis to other organs. These genes and the correlated oxidative phosphorylation pathway require further validation as potentially clinically useful predictors of BM and possibly as novel therapeutic targets for BM prevention.

Self-reported sleep quality as prognostic for survival in lung cancer patients.

PURPOSE: Sleep is essential for life, as well as having a major impact on quality of life. Not much attention has been given to this important factor in the care of lung cancer patients. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 404 lung cancer patients treated in our institute between 2010 and 2018. Data about sleep quality, distress and pain were self-reported by questionnaires administered to patients at their first clinic visit to the Institute of Oncology. Sex, age, histology, stage, smoking and marital status were extracted from the patients' charts. Uni- and multi-variate analyses were carried out to evaluate the correlation of these factors with survival. RESULTS: Most patients reported some level of distress and pain. Sleep abnormalities were reported by 58.7% of patients. Distress, pain and bad sleep were correlated with shorter survival in univariate analyses; however, only sleep remained associated with survival in multivariate analysis. Patients reporting bad sleep had a median survival of 16 months, compared to 27 months for patients reporting good sleep (hazard ratio 1.83, 95% C.I. 1.27-2.65). Frequent arousals at night were more tightly correlated with survival than difficulty falling asleep. CONCLUSION: Sleep quality, as reported by lung cancer patients, is highly correlated with survival. Further studies are required to comprehend whether poor sleep quality is directly impacting survival or is a result of the cancer aggressiveness and patients' conditions.

Transformation to small cell lung cancer as a mechanism of resistance to immunotherapy in non-small cell lung cancer.

OBJECTIVES: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death world-wide. Immune checkpoint inhibitors (ICI) have become the most promising type of treatment in oncology in general, and significantly so in NSCLC. Limited data is available about mechanisms of primary resistance. Data is lacking about mechanisms involved in acquired resistance or mixed responses in NSCLC. We aimed to identify mechanisms of resistance by studying biopsies taken from sites of secondary progression. MATERIALS AND METHODS: We identified all cases of NSCLC that have received ICI for advanced disease in our institute. Of these cases, those that have demonstrated acquired resistance or mixed responses, and have underwent a biopsy from a progressive lesion were analyzed. Selected specimens were subjected to next-generation sequencing (NGS; Oncomine™ Solid Tumour Fusion Transcript Kit). RESULTS: Out of 664 lung cancer cases, 249 were NSCLC that have received ICI. Of these, eight cases matched our search criteria. Two of them demonstrated transformation to small cell lung cancer (SCLC; 2/8, 25%). NGS verified a common origin to a matched pre-treatment NSCLC specimen and an on-treatment progressive SCLC specimen. In two cases no tumor cells were found and in the remaining four the pathology was similar to the initial biopsy. In one of the cases of SCLC transformation platinum-etoposide chemotherapy was administered, with short-term benefit only and further disease progression. CONCLUSION: Mechanisms of acquired resistance to ICI include SCLC transformation. Repeat biopsies of progressing lesions after initial response or in cases of mixed response can shed light on mechanisms of resistance.

Correlation of body composition by computerized tomography and metabolic parameters with survival of nivolumab-treated lung cancer patients.

PURPOSE: Weight loss is a well-recognized prognostic parameter for survival of lung cancer patients. Computerized-tomography (CT)-based analysis of body composition and blood-based metabolic evaluation are promising prognostic tools. We aimed to assess the correlation between albumin, body mass index (BMI), skeletal muscle mass index (SMI), fat-free mass index (FFMI), fat mass index (FMI) and weight change, as well as their correlation with survival of lung cancer patients on nivolumab treatment. METHODS: Data were retrospectively collected. Weight was measured at a diagnosis of stage 4 disease and before start of nivolumab. Albumin levels were measured before starting nivolumab. BMI, SMI, FFMI, and FMI were evaluated from CT scans performed at start of nivolumab. Overall survival (OS) was from starting of nivolumab to death or censured at last follow-up. Statistical analysis was done to identify correlation between the various factors and between those factors and survival. RESULTS: Forty-six patients with advanced non-small cell lung cancer (NSCLC) were included. Median follow-up was 22 months. Pathology was Adenocarcinoma/Squamous/non-other specified in 25/15/6 respectively. All patients received nivolumab as an advanced-line treatment for stage IV NSCLC. We observed a significant correlation of weight loss (P=0.01, HR=2.85) and albumin (P=0.043, HR=0.34) with OS in multivariate analysis. A significant correlation was found between BMI to SMI, FFMI, FMI, and weight change. CONCLUSION: Weight loss and low albumin levels are significant negative prognostic factors for NSCLC patients on immunotherapy. CT-based parameters of body composition remain to be proven as more reliable than standard clinical parameters.

Acute vascular events as a possibly related adverse event of immunotherapy: a single-institute retrospective study.

AIM: Immune-related toxicities of immune checkpoint inhibitors (CPIs) require prompt diagnosis and treatment. Atherosclerosis has an inflammatory component; we speculated this inflammation could be enhanced by CPIs. We aimed to evaluate the risk of acute vascular events (AVEs) on CPIs. METHODS: Patients treated by CPIs in Sheba Medical Center (Israel) between January 2015 and May 2018 were retrospectively identified from electronic medical records. AVEs were identified and verified by chart review. Age, sex, diabetes, hypertension, smoking, dyslipidemia, previous AVE, renal failure, cancer type and specific treatments were evaluated as potential risk factors. AVE rate on CPIs was compared with that on chemotherapy or on combined chemo-immunotherapy in patients with lung adenocarcinoma. Survival of patients with AVEs was compared with that of patients without AVEs. RESULTS: CPI was administered to 1215 patients. AVEs within six months after CPI initiation occurred in 2.6% (95% confidence interval [CI]: 1.8-3.6) of patients, more common than in later time periods. In lung adenocarcinoma, event rate was 5.2% (95% CI: 2.8-9.2). Lung adenocarcinoma, prior AVE, hypertension and dyslipidemia were correlated with AVEs. AVE rate in patients with non-small cell lung cancer adenocarcinoma was similar whether on chemotherapy or on CPI. Survival of patients with AVEs was worse than that of those without AVEs. CONCLUSION: The similarly increased rates of AVEs for patients on CPI, on chemotherapy or on both suggest that although CPI may not augment the risk of AVE over that of chemotherapy, it carries a similar and significant risk of such adverse event. Caution should be exercised for patients with risk factors for AVEs.