Posts Tagged ‘Cancer and Genetics’

Lung Cancer Update

Larry H. Bernstein, MD, FCAP, Curator



Investigational Agent May Benefit Non-Small Cell Lung Cancer Patients With Leptomeningeal Disease

Korean researchers are now reporting they may have an important new weapon that can cross the blood-brain barrier and combat leptomeningeal disease. If verified in future studies, this could provide a whole new approach to treating patients with non-small cell lung cancer (NSCLC) with leptomeningeal disease.

The epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) AZD9291 has been found to cross the blood-brain barrier. This experimental agent also showed clinical activity in heavily pretreated NSCLC patients with leptomeningeal disease, according to data from a phase I BLOOM clinical trial presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Study results were also published April 30, 2015, in The New England Journal of Medicine.

Leptomeningeal disease, a disease in which lung cancer cells spread to the membranes surrounding the brain and spinal cord, is rare at initial diagnosis of NSCLC. “However, as their lung cancer progresses, up to 15% of patients will develop this devastating complication. Additionally, an increased risk of central nervous system (CNS) involvement has been reported among patients with EGFR-mutant NSCLC, in particular those treated with a first-generation EGFR-TKI,” said Dae Ho Lee, MD, PhD,  who is an associate professor in the Department of Oncology in the University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.

Dr. Lee said patients with EGFR-mutated NSCLC and leptomeningeal disease have an average survival of 7 to 11 months, and currently, there are no established effective treatments for this condition.

Of the 13 heavily pretreated EGFR-mutant NSCLC patients that Dr. Lee and colleagues enrolled in the phase I trial, 10 had received other EGFR-TKIs as prior therapies and seven had received radiotherapy to the brain. Among these patients, four had T790M-positive disease detected in their plasma and two had DNA with the T790M mutation detected in their cerebrospinal fluid (CSF). All patients received 160 mg of AZD9291 once daily until disease progression. Treatment beyond progression was allowed at investigator discretion.

“There is no standardized way to measure response of leptomeningeal disease to therapy, but a combination of clearing cancer cells from the fluid surrounding the brain (CSF cytology), changes on brain MRI imaging, and improvement in neurologic symptoms is likely to be the best composite endpoint to assess clinical benefit,” said Dr. Lee.

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Subset of Lung Cancer Patients Have Improved Outcomes with Tivantinib, Erlotinib Combination

Advanced lung cancer patients who have tumors with mutations in the epidermal growth factor receptor (EGFR) gene may benefit from the combination treatment of erlotinib standard therapy plus tivantinib.


The results of a preplanned subset analysis of a large phase III previously reported clinical trial were presented (abstract B194) at the International Conference on Molecular Targets and Cancer Therapeutics conference, held November 5-9, 2015, in Boston. This conference was organized by the American Association for Cancer Research and the National Cancer Institute.

The addition of tivantinib, an experimental, oral anticancer drug that has selective anti-c-Met activity, to the standard of care EGFR inhibitor ,erlotinib, improved progression-free survival (PFS), response rate, and also overall survival in some cases, compared to erlotinib alone in patients with previously treated, advanced, non-squamous, EGFR and MET inhibitor naive non-small cell lung cancer (NSCLC).

Previously published in the Journal of Clinical Oncology, results of the randomized phase III MARQUEE patient trial (1,048 enrolled) demonstrated that adding tivantinib to erlotinib treatment improved PFS, but did not improve overall survival compared to erlotinib alone in the overall study population. Patients in the erlotinib plus placebo arm had a median overall survival of 7.8 months compared to 8.5 months in the combination arm (P = .81).

Of the 109 patients on trial who had tumors positive for an EGFR mutation (56 assigned to the combination and 53 to the control arm), those treated with trivantinib had a median PFS of 13.0 months compared to 7.5 months in the control group (P = .0016).

Although not statistically significant, the overall response rate and median overall survival were also increased, from 43% to 61% and from 20.0 months to 25.5 months, respectively. According to Wallace Akerley, MD, director of thoracic oncology at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, greater numbers of patients give a greater chance to show small differences, so this subset analysis was capable of showing only major differences in outcome. Overall survival was also improved from 20.0 months to 25.5 months in the experimental group, although the difference was not statistically significant (P = 0.1).

– See more at: http://www.oncotherapynetwork.com/lung-cancer-targets/subset-lung-cancer-patients-have-improved-outcomes-tivantinib-erlotinib-combination#sthash.38XyIlNg.dpuf

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Investigators at Moffitt Cancer Center have found that STK11 gene mutations are associated with changes in immune surveillance genes, while TP53 mutations are associated with changes in proliferation genes.

There are four gene mutations (KRAS, TP53, STK11, and EGFR) that most commonly occur in lung cancer.  However, there are limited effective therapies to target these mutations. The researchers hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors.

They analyzed gene expression patterns in 442 lung adenocarcinomas and screened the tumors for gene mutations known to contribute to lung cancer development. They used this data to assess associations between genetic alterations, gene expression patterns, and clinical outcomes.

They found that 34.8% of lung tumors had KRAS mutations, 10.6% had mutations in EGFR, 15.3% in STK11, and 25.1% in TP53. Lung cancer patients who had KRAS mutations had a shorter survival than patients without KRAS mutations. They found that lung cancer patients who had EGFR mutations had a better overall survival (OS) than patients without EGFR mutations.

The study also revealed that tumors with either TP53 or STK11 mutations had different gene expression patterns. Lung tumors with TP53 mutations had higher levels of genes that are associated with proliferation and growth, while lung tumors with STK11 mutations had lower levels of genes that are associated with immune surveillance. They confirmed these results by showing that tumors with STK11 mutations had reduced levels of T cells.

– See more at: http://www.oncotherapynetwork.com/lung-cancer-targets/researchers-identify-genetic-mutations-associated-poor-outcomes-lung-cancer-patients

Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma
M B Schabath, E A Welsh, W J Fulp, L Chen, J K Teer, Z J Thompson, B E Engel, M Xie, et al.   Oncogene , (19 October 2015) | http://dx.doi.org:/10.1038/onc.2015.375

While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.


AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer

Pasi A. Jänne, James Chih-Hsin Yang, Dong-Wan Kim, David Planchard, et al.

N Engl J Med 2015; 372:1689-1699 April 30, 2015    DOI: http://dx.doi.org:/10.1056/NEJMoa1411817

Somatic mutations in the gene encoding epidermal growth factor receptor (EGFR) are detected in approximately 30 to 40% of non–small-cell lung cancers (NSCLCs) from Asian patients and in 10% of NSCLCs from white patients.1-3 EGFR mutations lead to constitutive activation of EGFR signaling and oncogenic transformation both in vitro and in vivo.4,5 Cancers with EGFR mutations (EGFR-mutated cancers) depend on EGFR signaling for growth and survival and are often sensitive to treatment with EGFR tyrosine kinase inhibitors.6 Among patients with advanced EGFR-mutated NSCLC, treatment with EGFR tyrosine kinase inhibitors (e.g., gefitinib, erlotinib, and afatinib) is associated with response rates of 56 to 74% and a median progression-free survival of 10 to 14 months; both outcomes are superior to those with platinum-based chemotherapy.7-10

Despite initial responses to EGFR tyrosine kinase inhibitors, the majority of patients will have disease progression within 1 to 2 years after treatment initiation (acquired resistance).7-10 In approximately 60% of patients, the mechanism of acquired resistance is the development of an additional EGFR mutation, EGFR T790M.11 This mutation leads to an enhanced affinity for ATP, thus reducing the ability of ATP-competitive reversible EGFR tyrosine kinase inhibitors, including gefitinib and erlotinib, to bind to the tyrosine kinase domain of EGFR.12 One strategy to overcome this mechanism of resistance is through the use of irreversible EGFR inhibitors.13 Although the irreversible EGFR inhibitors afatinib and dacomitinib have been shown to be effective in preclinical models, they are associated with response rates of less than 10% and a progression-free survival of less than 4 months in patients with NSCLC who have received previous treatment with gefitinib or erlotinib, probably owing to an inability of afatinib or dacomitinib to inhibit EGFR T790M at clinically achievable doses.14-17 In addition, the potent inhibition of wild-type EGFR by these agents is associated with skin and gastrointestinal toxic effects.18,19 Treatment options after the failure of an EGFR tyrosine kinase inhibitor are thus limited and include cytotoxic chemotherapy or supportive care.20

AZD9291 (AstraZeneca) is an oral, potent, irreversible EGFR tyrosine kinase inhibitor that is selective for EGFR tyrosine kinase inhibitor–sensitizing mutations and the T790M resistance mutation (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).21 As compared with previous EGFR inhibitors, AZD9291 shows significantly less in vitro activity against wild-type EGFR.21 In studies involving genetically engineered mouse models of EGFR-mutated NSCLC, AZD9291 had antitumor activity in EGFR L858R tumors that was similar to that of afatinib, but AZD9291 was significantly more effective than afatinib in EGFR L858R tumors that had a concurrent T790M mutation.21 This suggests that AZD9291 may be effective in patients with EGFR-mutated NSCLC in whom T790M-mediated resistance to EGFR inhibitors had developed. We conducted a phase 1 study to determine the safety and efficacy of AZD9291 in patients with advanced EGFR-mutated NSCLC in whom resistance to treatment with EGFR tyrosine kinase inhibitors had developed.



Progression-free Survival According to Status with Respect to EGFR T790M.


The development of drug resistance is a major barrier to the successful long-term treatment of patients with EGFR-mutated NSCLC. Strategies to treat patients with EGFR T790M, the most common cause of acquired drug resistance, have been hampered by both lack of efficacy and dose-limiting toxic effects.16,17 Among the most effective strategies to date, the combination of afatinib and cetuximab is associated with a response rate of 29% (32% among patients with EGFR T790M and 25% among patients without it) but is associated with substantial skin toxic effects (20% of grade 3 or higher) and gastrointestinal toxic effects (6% of grade 3 or higher).23 In contrast, we found that AZD9291 as monotherapy was associated with a response rate of 61%, with limited skin and gastrointestinal adverse effects, among patients withEGFR T790M. This suggests that a structurally distinct EGFR inhibitor, one that is selective for the mutated form of EGFR, can be clinically effective and has a side-effect profile that is not dose-limiting in the majority of patients in whom T790M-mediated drug resistance had developed. It has long been recognized that EGFR T790M is a drug-resistance mechanism, but our study provides clinical evidence that the presence of T790M causes resistance to EGFR tyrosine kinase inhibitors.

The primary objective of this study was to assess the safety and efficacy of AZD9291. The 20-mg starting dose was selected on the basis of preclinical toxicology data and xenograft models that predicted that this dose would be sufficient to inhibit EGFR T790M, whereas doses equivalent to 80 mg or more were expected to lead to more profound inhibition of tumor growth.21 AZD9291 treatment led to similar response rates among patients with detectable EGFR T790M across all dose levels. As suggested by the preclinical studies, AZD9291 treatment was associated with limited skin and gastrointestinal adverse effects. At the 160-mg and 240-mg dose levels, there was an increase in the incidence and severity of adverse events associated with inhibition of nonmutant EGFR, including rash, dry skin, pruritus, and diarrhea. This suggests that at these dose levels, AZD9291 is starting to inhibit wild-type EGFR more significantly in patients. The dose of 80 mg once daily is being evaluated further as a single agent in patients with detectable EGFR T790M (ClinicalTrials.gov numbers, NCT02094261 and NCT0215198). ….

Acquired resistance to EGFR tyrosine kinase inhibitors is mediated by non-T790M mechanisms in approximately 40% of cancers.11 Although the mechanisms are not fully understood, known mechanisms include activation of non-EGFR bypass signaling pathways and histologic transformation (epithelial-to-mesenchymal transformation or transformation to small-cell lung cancer); in some instances, these mechanisms may be due to tumor heterogeneity. AZD9291 was associated with a response rate of 21% among patients without detectable EGFR T790M and a lower rate (11%) among patients who were T790M-negative and had received an EGFR tyrosine kinase inhibitor as the last treatment regimen before study entry. Thus, one reason for the activity of AZD9291 in patients without detectable EGFR T790M may be a retreatment effect after a “holiday” from treatment with an EGFR tyrosine kinase inhibitor, as reported previously in some studies of gefitinib.24

Current approaches to address cancers that are resistant to EGFR tyrosine kinase inhibitors with non–T790M-dependent resistance mechanisms include investigation of the combination of an EGFR inhibitor and a MET inhibitor; this combination, however, has been limited by both toxic effects and a lack of efficacy.25,26 The activity of AZD9291 coupled with its safety profile may provide the opportunity to evaluate combination treatment strategies, including with MET inhibitors, to further improve clinical outcomes in patients with resistance to EGFR tyrosine kinase inhibitors.

In summary, AZD9291 was associated with tumor responses in the majority of patients with advanced NSCLC in whom T790M-mediated drug resistance had developed.


3 MARQUEE study

Giorgio V. Scagliotti1, Sergey Orlov2, Joachim von Pawel3, Frances A. Shepherd4, Wallace Akerley5, et al

Background: Erlotinib is highly effective for EGFR mutant lung cancer, but invariably, all tumors develop resistance. Tivantinib was evaluated in combination with erlotinib for non-squamous NSCLC in the biomarker-unselected Phase 3 MARQUEE study. The objective of this exploratory analysis was to evaluate the safety and efficacy of tivantinib when combined with erlotinib for treatment of EGFR mutant NSCLC.
Methods: Patients with advanced non-squamous, EGFR and MET inhibitor naive NSCLC previously treated with 1-2 lines of systemic therapy, including a platinum-doublet, were stratified by number of prior therapies, sex, smoking history, and EGFR and KRAS mutation status, then randomized to oral tivantinib (360 mg twice daily) + erlotinib (150 mg once daily) (T+E) or placebo + erlotinib (P+E) and treated until disease progression. For this analysis, the EGFR mutant subpopulation continued to be managed consistent with the original protocol after the study in the rest of the population was completed. A data-cut was defined in advance to occur at ~2.5 years after the last patient was randomized. Testing for EGFR genotype in pre-treatment tumor tissue was performed at a central laboratory; existing EGFR results were acceptable if they met validation criteria. Key efficacy measures included PFS, OS, and objective response rate (ORR). Safety measures included the incidence of common and Grade 3/4 adverse events.
Results: In the overall study, 1048 patients were randomized. EGFR genotype was known for 99.8%; 109 (10.4%) patients (56 T+E, 53 P+E) had EGFR mutant disease, and all are included in this analysis. Patient characteristics within the EGFR mutant subgroup were generally balanced between T+E and P+E arms, respectively; median age: 60 vs 65 y, female: 57% vs 53%, Caucasian: 82% vs 83%, Asian: 3.6% vs 3.8%, never smoker: 48% vs 60%, one prior therapy: 70% vs 76%, and ECOG performance status of 0: 38% vs 32%. Addition of tivantinib to erlotinib substantially increased PFS in this population; median PFS was 13.0 and 7.5 months for T+E and P+E, respectively (hazard ratio [HR] 0.49; 95% CI, 0.31-0.77; p=0.0016). At the data cut-off, 6 patients remained on study treatment, all in the T+E arm (10.4%). Deaths had occurred in 73 (67%) subjects, and OS tended to be longer with tivantinib. Median OS was 25.5 and 20.0 months, respectively (HR=0.68; 95% CI, 0.43-1.08; p=0.10). ORR was higher at 61% (95% CI, 48-72%) for T+E compared with 43% (95% CI, 31-57%) for P+E. The most common reason for treatment discontinuation was progressive disease for both treatment arms. Common adverse events included diarrhea (39.3% vs 43.4%), rash (35.7% vs 39.6%), and asthenia/fatigue (30.4% vs 25.4%), which occurred at similar rates between treatments. Neutropenia (Grade 3/4: 16.1% vs 5.7%) and febrile neutropenia (3.6% vs 0%) were more common with T+E as expected.
Conclusion: Tivantinib combined with erlotinib was well tolerated and increased the efficacy of erlotinib for EGFR mutant NSCLC in this exploratory analysis.



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