Background Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction. Patients and methods We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation. Results We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS ( n = 271), EGFR ( n = 125), BRAF ( n = 43), MET ( n = 36), HER2 ( n = 29), ALK ( n = 23), RET ( n = 16), ROS1 ( n = 7), and multiple drivers ( n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR , 3.2 for KRAS , 2.5 for ALK , 3.1 for BRAF , 2.5 for HER2 , 2.1 for RET , and 3.4 for MET . In certain subgroups, PFS was positively associated with PD-L1 expression ( KRAS , EGFR ) and with smoking status ( BRAF , HER2 ). Conclusions : ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in th...

In vivo–based functional genomic screen identifies DDR2 as an important determinant of efficacy of anti–PD-1 immunotherapy.

BackgroundThere is a paucity of literature about the benefits of bone-targeted agents for breast cancer patients with bone metastases treated in the non-trial setting. We explored the incidence, consequences, and treatment of bone metastases at a single cancer centre.MethodsElectronic records of metastatic breast cancer patients were reviewed and pertinent information was extracted.ResultsOf 264 metastatic breast cancer patients, 195 (73%) developed bone metastases. Of these patients, 176 were eligible for analysis. Median age at bone metastases diagnosis was 56.9 years (IQR 48–67) and initial presentation of bone metastases included asymptomatic radiological findings (58%), bone pain (40%), or a SRE (12.5%). Most patients (88%) received a bone-targeted agent, starting a median of 1.5 months (IQR 0.8–3.30) after bone metastasis diagnosis. 62% of patients had ≥1 SRE. The median time from bone metastasis diagnosis to first SRE was 1.8 months (IQR 0.20–8.43 months). Median number of SREs per patient was 1.5 (IQR 0–3). Overall, 26.8% of all SREs were clinically asymptomatic. Within the entire cohort, 51% required opioids and 20% were hospitalized due to either an SRE or bone pain.ConclusionsDespite extensive use of bone-targeted agents, the incidence of SREs remains high. Nearly half of SREs occur prior to starting a bone-targeted agent. Use of opioids and hospitalizations secondary to bone metastases remain common. More effective treatment options are clearly needed.

Introduction: This study aims to determine whether advanced ROS1 gene-rearranged NSCLC (ROS1þ NSCLC) has a higher than expected thromboembolic event (TEE) rate.Methods: Venous and arterial TEEs within ±365 days of diagnosis of ROS1þ, ALKþ, EGFRþ, or KRASþ advanced NSCLC at five academic centers in the United States and China were captured (October 2002-April 2018). The primary endpoint was incidence of TEE in ROS1þ compared to anaplastic lymphoma kinase (ALK)þ, EGFRþ, and KRASþ NSCLC within ±90 days of diagnosis. Logistic regression was used to assess if the odds of TEE differed among oncogene drivers.Results: Eligible data from 95 ROS1þ, 193 ALKþ, 300 EGFRþ, and 152 KRASþ NSCLC patients were analyzed. The incidence rate of TEE was 34.7% (n ¼ 33), 22.3% (n ¼ 43), 13.7% (n ¼ 41), and 18.4% (n ¼ 28), respectively. In univariate analysis, the odds of a TEE in ROS1þ NSCLC were higher than ALKþ, EGFRþ, and KRASþ cohorts. In multivariable analysis, the odds of a TEE were significantly higher for ROS1þ compared to EGFRþ and KRASþ cohorts, the odds ratio (OR) was 2.44, with a 95% confidence interval of 1.31-4.57 (p ¼ 0.005), and OR: 2.62, with a 95% confidence interval of 1.26-5.46 (p ¼ 0.01), respectively.Although numerically superior, the odds for a TEE with ROS1þ compared to ALKþ was not statistically significant (OR: 1.45, p ¼ 0.229). Overall survival was not significantly

Background. Many cancer patients receive supplemental ascorbate (vitamin C) in the belief that it synergizes the anticancer effects of chemotherapy and reduces its toxicity. Methods. A systematic review was performed to evaluate the antitumor effects and toxicity of ascorbate treatment. Medline (1946 to March 2014), EMBASE (1947 to March 2014), and the Cochrane central register (1993 to March 2014) were searched for randomized and observational studies. Results. Of 696 identified records, 61 full‐text articles were screened and 34 were included. In total, 5 randomized controlled trials (RCTs) (n = 322), 12 phase I/II trials (n = 287), 6 observational studies (n = 7,599), and 11 case reports (n = 267) were identified. Because of study heterogeneity, no meta‐analyses were performed. No RCTs reported any statistically significant improvements in overall or progression‐free survival or reduced toxicity with ascorbate relative to control arm. Evidence for ascorbate's antitumor effects was limited to case reports and observational and uncontrolled studies. Conclusion. There is no high‐quality evidence to suggest that ascorbate supplementation in cancer patients either enhances the antitumor effects of chemotherapy or reduces its toxicity. Given the high financial and time costs to patients of this treatment, high‐quality placebo‐controlled trials are needed.