Gabriel Rivera

KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study.

EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.

Risk Stratification for Second Primary Lung Cancer

Purpose This study estimated the 10-year risk of developing second primary lung cancer (SPLC) among survivors of initial primary lung cancer (IPLC) and evaluated the clinical utility of the risk prediction model for selecting eligibility criteria for screening. Methods SEER data were used to identify a population-based cohort of 20,032 participants diagnosed with IPLC between 1988 and 2003 and who survived ≥ 5 years after the initial diagnosis. We used a proportional subdistribution hazards model to estimate the 10-year risk of developing SPLC among survivors of lung cancer LC in the presence of competing risks. Considered predictors included age, sex, race, treatment, histology, stage, and extent of disease. We examined the risk-stratification ability of the prediction model and performed decision curve analysis to evaluate the clinical utility of the model by calculating its net benefit in varied risk thresholds for screening. Results Although the median 10-year risk of SPLC among survivors of LC was 8.36%, the estimated risk varied substantially (range, 0.56% to 14.3%) when stratified by age, histology, and extent of IPLC in the final prediction model. The stratification by deciles of estimated risk showed that the observed incidence of SPLC was significantly higher in the tenth-decile group (12.5%) versus the first-decile group (2.9%; P < 10-10). The decision curve analysis yielded a range of risk thresholds (1% to 11.5%) at which the clinical net benefit of the risk model was larger than those in hypothetical all-screening or no-screening scenarios. Conclusion The risk stratification approach in SPLC can be potentially useful for identifying survivors of LC to be screened by computed tomography. More comprehensive environmental and genetic data may help enhance the predictability and stratification ability of the risk model for SPLC.

Lung Cancer in Never Smokers

Lung cancer is predominantly associated with cigarette smoking; however, a substantial minority of patients with the disease have never smoked. In the US it is estimated there are 17,000-26,000 annual deaths from lung cancer in never smokers, which as a separate entity would be the seventh leading cause of cancer mortality. Controversy surrounds the question of whether or not the incidence of lung cancer in never-smokers is increasing, with more data to support this observation in Asia. There are several factors associated with an increased risk of developing lung cancer in never smokers including second hand smoke, indoor air pollution, occupational exposures, and genetic susceptibility among others. Adenocarcinoma is the most common histology of lung cancer in never smokers and in comparison to lung cancer in smokers appears less complex with a higher likelihood to have targetable driver mutations.

Immune checkpoint pathways: perspectives on myeloid malignancies.

Abstract Immunologic tolerance to cancer has recently been shown to have major implications for the ability of tumors to survive despite a variety of therapeutic approaches. A critical mechanism underlying this microenvironment dysfunction relates to the ability of tumor cells to block immune check points through expression of specific proteins that interfere with immune cell effector function. Recent advances based on this model have led translational work showing therapeutic efficacy in a variety of solid and lymphoid tumors. Myeloid malignancies, in particular myelodysplastic syndromes (MDS), have significant immune dysregulation of variable degree based on their clinical stages which makes feasible extending such therapeutic approaches to this group of diseases. This review will discuss recent advances in the field of immune checkpoint biology including recent clinical trials with checkpoint inhibitors in patients with a variety of clinical conditions, with focus on such potential therapy in patients with myeloid malignancies.

Overcoming Resistance Without the Risk of Reaction: Use of Afatinib and Panitumumab in Two Cases of Epidermal Growth Factor Receptor--Mutated Non--Small-Cell Lung Cancer With T790M Mutations.

Patients with acquired resistance to first-generation EGFR TKIs, including those with the T790M mutation, may still respond to EGFR-targeted therapy. Combination afatinib and panitumumab may represent a viable therapeutic option for patients with acquired resistance to first-generation EGFR TKIs. Optimal management of LMC is an ongoing challenge, and the efficacy of targeted therapies remains undefined.

PS01.77: Risk-Stratification for Second Primary Lung Cancer

Background: Chemotherapy is well established to improve survival in patients with advanced nonesmall cell lung cancer (NSCLC). However, the importance of chemotherapy dose intensity in this setting remains controversial. This study looked at the clinical impact of chemotherapy dosing and schedule on survival. Methods: Systematic PubMed literature search of randomized controlled trials (RCTs) in adult patients with lung cancer published between 1990 and 2014 was conducted. RCTs in advanced stage NSCLC using chemotherapy in at least one arm were sought. Metaanalysis comparing more intense myelosuppressive regimens with less intense ones was employed. Relative risks of progression and mortality at 6 and 12 months were estimated by random effects models. Heterogeneity was assessed by the Inconsistency Index I. Results: A total of 3328 studies were identified, and 127 studies (26,208 patients) were determined eligible. RCTs were classified based on 7 design groups (Table). Average median progression-free (PFS) and overall (OS) survivals were 4.0 and 8.6 months, respectively. Improved PFS and OS at 6 and 12monthswere observedwith addition of 1 or more chemotherapy agents to single drug regimens. Similarly, improvement in both PFS and OS at 6 and 12 months was detected when use of chemotherapy was compared with best supportive care (BSC). Addition of 1 or more chemotherapy agents to multidrug regimens improved PFS, but not OS.More cycles had a positive effect on early PFS andOS. Chemotherapy vs. BSC after induction improved PFS and OS at 1 year. Conclusion: Chemotherapy intensity can impact both PFS and OS in NSCLC. In addition to the known benefit of chemotherapy vs. best supportive care, the addition of chemotherapeutics improves survival. More cycles of the same chemotherapy showed limited, early clinical benefit.

Poster SessionsPS01.77: Risk-Stratification for Second Primary Lung Cancer: Topic: Medical Oncology

Background: Chemotherapy is well established to improve survival in patients with advanced nonesmall cell lung cancer (NSCLC). However, the importance of chemotherapy dose intensity in this setting remains controversial. This study looked at the clinical impact of chemotherapy dosing and schedule on survival. Methods: Systematic PubMed literature search of randomized controlled trials (RCTs) in adult patients with lung cancer published between 1990 and 2014 was conducted. RCTs in advanced stage NSCLC using chemotherapy in at least one arm were sought. Metaanalysis comparing more intense myelosuppressive regimens with less intense ones was employed. Relative risks of progression and mortality at 6 and 12 months were estimated by random effects models. Heterogeneity was assessed by the Inconsistency Index I. Results: A total of 3328 studies were identified, and 127 studies (26,208 patients) were determined eligible. RCTs were classified based on 7 design groups (Table). Average median progression-free (PFS) and overall (OS) survivals were 4.0 and 8.6 months, respectively. Improved PFS and OS at 6 and 12monthswere observedwith addition of 1 or more chemotherapy agents to single drug regimens. Similarly, improvement in both PFS and OS at 6 and 12 months was detected when use of chemotherapy was compared with best supportive care (BSC). Addition of 1 or more chemotherapy agents to multidrug regimens improved PFS, but not OS.More cycles had a positive effect on early PFS andOS. Chemotherapy vs. BSC after induction improved PFS and OS at 1 year. Conclusion: Chemotherapy intensity can impact both PFS and OS in NSCLC. In addition to the known benefit of chemotherapy vs. best supportive care, the addition of chemotherapeutics improves survival. More cycles of the same chemotherapy showed limited, early clinical benefit.

PS01.77: Risk-Stratification for Second Primary Lung Cancer: Topic: Medical Oncology

Background: Chemotherapy is well established to improve survival in patients with advanced nonesmall cell lung cancer (NSCLC). However, the importance of chemotherapy dose intensity in this setting remains controversial. This study looked at the clinical impact of chemotherapy dosing and schedule on survival. Methods: Systematic PubMed literature search of randomized controlled trials (RCTs) in adult patients with lung cancer published between 1990 and 2014 was conducted. RCTs in advanced stage NSCLC using chemotherapy in at least one arm were sought. Metaanalysis comparing more intense myelosuppressive regimens with less intense ones was employed. Relative risks of progression and mortality at 6 and 12 months were estimated by random effects models. Heterogeneity was assessed by the Inconsistency Index I. Results: A total of 3328 studies were identified, and 127 studies (26,208 patients) were determined eligible. RCTs were classified based on 7 design groups (Table). Average median progression-free (PFS) and overall (OS) survivals were 4.0 and 8.6 months, respectively. Improved PFS and OS at 6 and 12monthswere observedwith addition of 1 or more chemotherapy agents to single drug regimens. Similarly, improvement in both PFS and OS at 6 and 12 months was detected when use of chemotherapy was compared with best supportive care (BSC). Addition of 1 or more chemotherapy agents to multidrug regimens improved PFS, but not OS.More cycles had a positive effect on early PFS andOS. Chemotherapy vs. BSC after induction improved PFS and OS at 1 year. Conclusion: Chemotherapy intensity can impact both PFS and OS in NSCLC. In addition to the known benefit of chemotherapy vs. best supportive care, the addition of chemotherapeutics improves survival. More cycles of the same chemotherapy showed limited, early clinical benefit.