American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting, 2015
Although there once was a single algorithm for the treatment of patients with advanced lung cance... more Although there once was a single algorithm for the treatment of patients with advanced lung cancer, the modern treatment of advanced lung cancer has multiple treatment pathways that depend on multiple factors, including histology and molecular subtype of disease. New molecular targets, targeted agents, and modes of therapy for patients, including immunotherapy, are being identified at an accelerating pace. These advances are changing outcomes and the treatment landscape, but they also highlight situations with inadequate data to support the use of cytotoxic chemotherapy. In this article, we provide an overview of data regarding cytotoxic chemotherapy and targeted therapy and their value after second line, review the critical role of supportive care and palliative care, and emphasize the importance of advance care planning with our patients. Although this article focuses primarily on NSCLC, the comments about palliative care and advanced care planning also apply to patients with smal...
Proper expression of the human platelet fibrinogen receptor is necessary for the maintenance of n... more Proper expression of the human platelet fibrinogen receptor is necessary for the maintenance of normal hemostasis. This receptor is formed by the heterodimer alpha IIb beta 3, a prototypic member of the integrin family of adhesive molecules. beta 3 is also expressed in other tissues with alpha v as the vitronectin receptor. It was not possible to study the basis for tissue-specific expression of this gene, because the beta 3 gene promoter had not been isolated previously. We have now isolated a 6.0-kb human genomic DNA fragment containing 2.0 kb of sequence 5' to the beta 3 ATG start codon. This clone also contains sequence encoding the signal peptide of the immature beta 3 protein and 3.0 kb of 3' intronic sequence. Primer extension and RNase protection studies of poly A+ RNA from a human erythroleukemia (HEL) cell line indicated a major transcription start site 30 bp upstream of the ATG start codon. In an orientation-dependent manner, a 584-bp fragment 5' to the start ...
Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cel... more Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied. Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1). At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases. Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.
Small cell lung cancers (SCLCs) are characterized by aberrantly methylated O(6)-methyl-guanine-DN... more Small cell lung cancers (SCLCs) are characterized by aberrantly methylated O(6)-methyl-guanine-DNA methyltransferase (MGMT). Epigenetic silencing of MGMT is associated with loss of MGMT activity and improved sensitivity to alkylating agents in glioblastomas. We have reported the activity of temozolomide, a non-classical alkylating agent, in patients with relapsed sensitive or refractory SCLCs, given at 75 mg/m2/day for 21 of 28 days. However, prolonged myelosuppression was noted. We therefore evaluated a 5-day dosing schedule of temozolomide and examined MGMT as a predictive biomarker for temozolomide treatment in SCLC. Patients with sensitive or refractory SCLCs and progression after one or two prior chemotherapy regimens received temozolomide 200 mg/m2/day for 5 consecutive days in 28-day cycles. The primary endpoint was tolerability. We also assessed MGMT promoter methylation status by PCR and MGMT expression by immunohistochemistry in tumor specimens. Of 25 patients enrolled, 5 experienced grade 3 or 4 toxicity (anemia, thrombocytopenia, neutropenia, and constipation). The partial response rate was 12% [95% CI: 3-31%], with partial responses in 2 refractory patients. We were able to obtain tumor samples for more than half of patients for MGMT testing. Temozolomide 200 mg/m2/day for 5 days in 28-day cycles is tolerable and active in patients with relapsed SCLCs. No treatment-limiting prolonged cytopenias were observed, making this our preferred schedule for further studies. Acquisition of archived biospecimens is feasible and necessary in order to continue evaluating the role of MGMT as a predictive biomarker in SCLCs.
Background Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have... more Background Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progressionfree survival of 8-11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib.
Background-ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (... more Background-ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period.
No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We in... more No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We investigated the efficacy of cixutumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor 1 receptor in thymic epithelial tumours after failure of previous chemotherapy. Between Aug 25, 2009, and March 27, 2012, we did a multicentre, open-label, phase 2 trial in patients aged 18 years or older with histologically confirmed recurrent or refractory thymic epithelial tumours. We enrolled individuals who had progressed after at least one previous regimen of platinum-containing chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had measurable disease and adequate organ function. Eligible patients received intravenous cixutumumab (20 mg/kg) every 3 weeks until disease progression or development of intolerable toxic effects. The primary endpoint was the frequency of response, analysed on an intention-to-treat basis. We also did pharmacodynamic studies. This trial is registered with ClinicalTrials.gov, number NCT00965250. 49 patients were enrolled (37 with thymomas and 12 with thymic carcinomas) who received a median of eight cycles of cixutumumab (range 1-46). At the final actuarial analysis when follow-up data were updated (Nov 30, 2012), median potential follow-up (from on-study date to most current follow-up date) was 24·0 months (IQR 17·3-36·9). In the thymoma cohort, five (14%) of 37 patients (95% CI 5-29) achieved a partial response, 28 had stable disease, and four had progressive disease. In the thymic carcinoma cohort, none of 12 patients (95% CI 0-26) had a partial response, five had stable disease, and seven had progressive disease. The most common grade 3-4 adverse events in both cohorts combined were hyperglycaemia (five [10%]), lipase elevation (three [6%]), and weight loss, tumour pain, and hyperuricaemia (two each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions during treatment (five were new-onset disorders), the most common of which was pure red-cell aplasia. Two (4%) patients died; one was attributed to disease progression and the other to disease-related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Cixutumumab monotherapy is well-tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Division of Cancer Treatment and Diagnosis at the National Cancer Institute (National Institutes of Health), ImClone Systems.
The promise of effective targeted therapy for lung cancer requires rigorous identification of pot... more The promise of effective targeted therapy for lung cancer requires rigorous identification of potential targets combined with intensive discovery and development efforts aimed at developing effective "drugs" for these targets. We now recognize that getting the right drug to the right target in the right patient is more complicated than one could have imagined a decade ago. As knowledge of targets and development of agents have proliferated and advanced, so too have data demonstrating the biologic heterogeneity of tumors. The finding that lung cancers are genetically diverse and can exhibit several pathways of resistance in response to targeted agents makes the prospect for curative therapy more daunting. It is becoming increasingly clear that single-agent treatment will be the exception rather than the rule. This information raises important new questions about the development and assessment of novel agents in lung cancer treatment: (1) How do we identify the most important drug targets for tumor initiation and maintenance? (2) What is the best way to assess drug candidates that may only be relevant in a small fraction of patients? (3) What models do we use to predict clinical response and identify effective combinations? And (4) how do we bring combination regimens to the clinic, particularly when the agents are not yet approved individually and may be under development from different companies? The Fifth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer was held in Cambridge, Massachusetts, on October 1-2, 2007, to discuss these questions by reviewing recent progress in the field and advancing recommendations for research and patient care. New information, conclusions, and recommendations considered significant for the field by the program faculty are summarized here and presented at greater length in the individual articles and accompanying discussions that comprise the full conference proceedings. A CME activity based on this summary is also available at www.informedicalcme.com/cme.
Inhibiting epidermal growth factor receptor (EGFR) signaling has proven to be an effective strate... more Inhibiting epidermal growth factor receptor (EGFR) signaling has proven to be an effective strategy for treating non-small cell lung cancer (NSCLC) patients and the first generation of agents developed for this purpose, gefitinib and erlotinib, stimulated a unique escalation in both biologic and clinical research within the field. Second-generation EGFR-targeted agents that aim to further improve patient outcomes are now in preclinical and clinical trials. This review discusses four promising agents that are currently being studied in NSCLC: EKB-569, HKI-272, CI-1033, and ZD6474.
The tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective in non-small cell lun... more The tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective in non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) gene mutations. The usual clinical dose of gefitinib (250 mg/d) is only one third of its maximum tolerated dose, whereas the dose of erlotinib (150 mg/d) is at its maximum tolerated dose. In NSCLC cell lines, both TKIs have similar micromolar inhibitory concentrations. We explored whether erlotinib at 25 mg/d (trough serum concentration similar to gefitinib 250 mg/d) would be efficacious in EGFR-mutated NSCLC. To study the inhibitory concentrations of gefitinib and erlotinib, we exposed EGFR-mutated cell lines (HCC827, H3255, PC-9, and H1975) to increasing concentrations of these TKIs. Further on, we performed a retrospective evaluation of seven patients with advanced EGFR-mutated (exon 19 deletions and L858R) NSCLC that were given erlotinib at 25 mg/d as their first EGFR TKI. Gefitinib and erlotinib generated similar inhibitory curves across our panel of EGFR-mutated NSCLC cell lines with overlapping mean 50% inhibitory concentration 95% confidence intervals for HCC827, PC-9, and H1975. Both drugs also displayed a high degree of correlation in mean 50% inhibitory concentration (Pearson's r = 0.99, p = 0.0417). Of the seven patients, five patients (71.5%) had partial responses to erlotinib 25 mg/d. Median progression-free survival was 17 months (95% confidence interval, 6-35 months). Toxicities were minimal, with only two (28.5%) patients having a rash and none experiencing (0%) diarrhea. In NSCLC cell lines, gefitinib and erlotinib have similar inhibitory profiles. In patients with NSCLC and EGFR-activating mutations, a dose of erlotinib 25 mg/d (equivalent to gefitinib 250 mg/d) leads to impressive response rates and progression-free survival similar to the growing experience with the approved doses of gefitinib (250 mg/d) and erlotinib (150 mg/d). Identifying prospectively the lowest and clinically active dose ranges of erlotinib and gefitinib will help further to personalize care for patients with tumors harboring EGFR mutations.
International Journal of Radiation Oncology*Biology*Physics, 2014
Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastas... more Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole brain RT (WBRT), and 15 with stereotactic radiosurgery (SRS). The median overall survival (OS) for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median, 35 vs 26 months; P=.62), whereas patients treated with SRS had a longer OS than did those in the erlotinib group (median, 64 months; P=.004). The median time to intracranial progression was 17 months. There was a longer time to intracranial progression in patients who received WBRT than in those who received erlotinib upfront (median, 24 vs 16 months, P=.04). Patients in the erlotinib or SRS group were more likely to experience intracranial failure as a component of first failure, whereas WBRT patients were more likely to experience failure outside the brain (P=.004). The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system activity.
Journal of the National Comprehensive Cancer Network : JNCCN, 2015
These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small ... more These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 13, 2015
AUY922 is an HSP90 inhibitor that causes degradation of HSP chaperones and their client proteins,... more AUY922 is an HSP90 inhibitor that causes degradation of HSP chaperones and their client proteins, including epidermal growth factor receptor. We conducted a phase I/II trial to evaluate AUY922 and erlotinib for patients with EGFR-mutant lung cancer and disease progression during erlotinib treatment. All patients had developed acquired resistance after treatment with erlotinib and underwent repeat tumor biopsies before study entry to assess for EGFR T790M. In phase I, 18 patients were treated with AUY922 intravenously once per week and erlotinib once per day in 28-day cycles using a 3 + 3 dose-escalation design. In phase II, 19 additional patients were treated at the maximum-tolerated dose. The primary end point of the phase II trial was complete plus partial response rate. In phase I (n = 18), three patients were treated in each cohort, except the highest-dose cohort (AUY922 70 mg and erlotinib 150 mg), which expanded to six patients because of a dose-limiting toxicity (ie, junction...
Prognostic variables are independently associated with survival and are fundamental to clinical t... more Prognostic variables are independently associated with survival and are fundamental to clinical trial design. In the current study, the authors evaluated the impact of stage of disease at the time of the initial diagnosis on overall survival (OS) in 2 independent, oncogene-defined cohorts. All patients with epidermal growth factor receptor (EGFR)-mutant and KRAS-mutant metastatic lung adenocarcinomas were identified through routine molecular testing from January 2005 through January 2011. Clinical characteristics were obtained. OS from the date of diagnosis of recurrent or de novo metastatic disease was estimated using the Kaplan-Meier method. A total of 635 patients with KRAS-mutant and 496 patients with EGFR-mutant metastatic lung adenocarcinomas were identified. Among patients with KRAS-mutant lung adenocarcinomas, those with de novo metastatic disease were found to have a shorter median OS compared with those with recurrent metastatic disease (13 months vs 18 months; P = .003). ...
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting, 2012
Thymic carcinomas represent approximately 10% of thymic tumors. In our approach to patients with ... more Thymic carcinomas represent approximately 10% of thymic tumors. In our approach to patients with thymic carcinoma, we emphasize multimodality treatment with close communication between the pathologist, thoracic surgeon, medical oncologist, and radiation oncologist. Given the paucity of high-quality clinical research data, treatment decisions are guided by a small amount of prospective trial data, retrospective reports, and clinical experience. Surgical management of thymic carcinoma must account for the more aggressive biology, higher degree of local invasion of neighboring structures, greater propensity for nodal metastasis, and higher risk of distant metastatic disease. Although surgical resection remains the most important component in the management of localized thymic tumors, radiation therapy (RT) may be used as adjuvant therapy after surgical resection or as the definitive treatment modality in patients who are deemed unresectable because of medical comorbidities or technical...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2006
In 2004, several investigators reported that somatic mutations in the epidermal growth factor rec... more In 2004, several investigators reported that somatic mutations in the epidermal growth factor receptor gene were associated with clinical responses to erlotinib and gefitinib in patients with non-small cell lung cancer. Since then, multiple groups have examined the biological properties that such mutations confer as well as the clinical relevance of these mutations in patients with non-small cell lung cancer. Although a tremendous amount of knowledge has been gained in the past 2 years, there remain a number of important epidemiologic, biological, and clinical questions.
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting, 2015
Although there once was a single algorithm for the treatment of patients with advanced lung cance... more Although there once was a single algorithm for the treatment of patients with advanced lung cancer, the modern treatment of advanced lung cancer has multiple treatment pathways that depend on multiple factors, including histology and molecular subtype of disease. New molecular targets, targeted agents, and modes of therapy for patients, including immunotherapy, are being identified at an accelerating pace. These advances are changing outcomes and the treatment landscape, but they also highlight situations with inadequate data to support the use of cytotoxic chemotherapy. In this article, we provide an overview of data regarding cytotoxic chemotherapy and targeted therapy and their value after second line, review the critical role of supportive care and palliative care, and emphasize the importance of advance care planning with our patients. Although this article focuses primarily on NSCLC, the comments about palliative care and advanced care planning also apply to patients with smal...
Proper expression of the human platelet fibrinogen receptor is necessary for the maintenance of n... more Proper expression of the human platelet fibrinogen receptor is necessary for the maintenance of normal hemostasis. This receptor is formed by the heterodimer alpha IIb beta 3, a prototypic member of the integrin family of adhesive molecules. beta 3 is also expressed in other tissues with alpha v as the vitronectin receptor. It was not possible to study the basis for tissue-specific expression of this gene, because the beta 3 gene promoter had not been isolated previously. We have now isolated a 6.0-kb human genomic DNA fragment containing 2.0 kb of sequence 5' to the beta 3 ATG start codon. This clone also contains sequence encoding the signal peptide of the immature beta 3 protein and 3.0 kb of 3' intronic sequence. Primer extension and RNase protection studies of poly A+ RNA from a human erythroleukemia (HEL) cell line indicated a major transcription start site 30 bp upstream of the ATG start codon. In an orientation-dependent manner, a 584-bp fragment 5' to the start ...
Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cel... more Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied. Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1). At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases. Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.
Small cell lung cancers (SCLCs) are characterized by aberrantly methylated O(6)-methyl-guanine-DN... more Small cell lung cancers (SCLCs) are characterized by aberrantly methylated O(6)-methyl-guanine-DNA methyltransferase (MGMT). Epigenetic silencing of MGMT is associated with loss of MGMT activity and improved sensitivity to alkylating agents in glioblastomas. We have reported the activity of temozolomide, a non-classical alkylating agent, in patients with relapsed sensitive or refractory SCLCs, given at 75 mg/m2/day for 21 of 28 days. However, prolonged myelosuppression was noted. We therefore evaluated a 5-day dosing schedule of temozolomide and examined MGMT as a predictive biomarker for temozolomide treatment in SCLC. Patients with sensitive or refractory SCLCs and progression after one or two prior chemotherapy regimens received temozolomide 200 mg/m2/day for 5 consecutive days in 28-day cycles. The primary endpoint was tolerability. We also assessed MGMT promoter methylation status by PCR and MGMT expression by immunohistochemistry in tumor specimens. Of 25 patients enrolled, 5 experienced grade 3 or 4 toxicity (anemia, thrombocytopenia, neutropenia, and constipation). The partial response rate was 12% [95% CI: 3-31%], with partial responses in 2 refractory patients. We were able to obtain tumor samples for more than half of patients for MGMT testing. Temozolomide 200 mg/m2/day for 5 days in 28-day cycles is tolerable and active in patients with relapsed SCLCs. No treatment-limiting prolonged cytopenias were observed, making this our preferred schedule for further studies. Acquisition of archived biospecimens is feasible and necessary in order to continue evaluating the role of MGMT as a predictive biomarker in SCLCs.
Background Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have... more Background Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progressionfree survival of 8-11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib.
Background-ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (... more Background-ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period.
No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We in... more No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We investigated the efficacy of cixutumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor 1 receptor in thymic epithelial tumours after failure of previous chemotherapy. Between Aug 25, 2009, and March 27, 2012, we did a multicentre, open-label, phase 2 trial in patients aged 18 years or older with histologically confirmed recurrent or refractory thymic epithelial tumours. We enrolled individuals who had progressed after at least one previous regimen of platinum-containing chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had measurable disease and adequate organ function. Eligible patients received intravenous cixutumumab (20 mg/kg) every 3 weeks until disease progression or development of intolerable toxic effects. The primary endpoint was the frequency of response, analysed on an intention-to-treat basis. We also did pharmacodynamic studies. This trial is registered with ClinicalTrials.gov, number NCT00965250. 49 patients were enrolled (37 with thymomas and 12 with thymic carcinomas) who received a median of eight cycles of cixutumumab (range 1-46). At the final actuarial analysis when follow-up data were updated (Nov 30, 2012), median potential follow-up (from on-study date to most current follow-up date) was 24·0 months (IQR 17·3-36·9). In the thymoma cohort, five (14%) of 37 patients (95% CI 5-29) achieved a partial response, 28 had stable disease, and four had progressive disease. In the thymic carcinoma cohort, none of 12 patients (95% CI 0-26) had a partial response, five had stable disease, and seven had progressive disease. The most common grade 3-4 adverse events in both cohorts combined were hyperglycaemia (five [10%]), lipase elevation (three [6%]), and weight loss, tumour pain, and hyperuricaemia (two each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions during treatment (five were new-onset disorders), the most common of which was pure red-cell aplasia. Two (4%) patients died; one was attributed to disease progression and the other to disease-related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Cixutumumab monotherapy is well-tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Division of Cancer Treatment and Diagnosis at the National Cancer Institute (National Institutes of Health), ImClone Systems.
The promise of effective targeted therapy for lung cancer requires rigorous identification of pot... more The promise of effective targeted therapy for lung cancer requires rigorous identification of potential targets combined with intensive discovery and development efforts aimed at developing effective "drugs" for these targets. We now recognize that getting the right drug to the right target in the right patient is more complicated than one could have imagined a decade ago. As knowledge of targets and development of agents have proliferated and advanced, so too have data demonstrating the biologic heterogeneity of tumors. The finding that lung cancers are genetically diverse and can exhibit several pathways of resistance in response to targeted agents makes the prospect for curative therapy more daunting. It is becoming increasingly clear that single-agent treatment will be the exception rather than the rule. This information raises important new questions about the development and assessment of novel agents in lung cancer treatment: (1) How do we identify the most important drug targets for tumor initiation and maintenance? (2) What is the best way to assess drug candidates that may only be relevant in a small fraction of patients? (3) What models do we use to predict clinical response and identify effective combinations? And (4) how do we bring combination regimens to the clinic, particularly when the agents are not yet approved individually and may be under development from different companies? The Fifth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer was held in Cambridge, Massachusetts, on October 1-2, 2007, to discuss these questions by reviewing recent progress in the field and advancing recommendations for research and patient care. New information, conclusions, and recommendations considered significant for the field by the program faculty are summarized here and presented at greater length in the individual articles and accompanying discussions that comprise the full conference proceedings. A CME activity based on this summary is also available at www.informedicalcme.com/cme.
Inhibiting epidermal growth factor receptor (EGFR) signaling has proven to be an effective strate... more Inhibiting epidermal growth factor receptor (EGFR) signaling has proven to be an effective strategy for treating non-small cell lung cancer (NSCLC) patients and the first generation of agents developed for this purpose, gefitinib and erlotinib, stimulated a unique escalation in both biologic and clinical research within the field. Second-generation EGFR-targeted agents that aim to further improve patient outcomes are now in preclinical and clinical trials. This review discusses four promising agents that are currently being studied in NSCLC: EKB-569, HKI-272, CI-1033, and ZD6474.
The tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective in non-small cell lun... more The tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective in non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) gene mutations. The usual clinical dose of gefitinib (250 mg/d) is only one third of its maximum tolerated dose, whereas the dose of erlotinib (150 mg/d) is at its maximum tolerated dose. In NSCLC cell lines, both TKIs have similar micromolar inhibitory concentrations. We explored whether erlotinib at 25 mg/d (trough serum concentration similar to gefitinib 250 mg/d) would be efficacious in EGFR-mutated NSCLC. To study the inhibitory concentrations of gefitinib and erlotinib, we exposed EGFR-mutated cell lines (HCC827, H3255, PC-9, and H1975) to increasing concentrations of these TKIs. Further on, we performed a retrospective evaluation of seven patients with advanced EGFR-mutated (exon 19 deletions and L858R) NSCLC that were given erlotinib at 25 mg/d as their first EGFR TKI. Gefitinib and erlotinib generated similar inhibitory curves across our panel of EGFR-mutated NSCLC cell lines with overlapping mean 50% inhibitory concentration 95% confidence intervals for HCC827, PC-9, and H1975. Both drugs also displayed a high degree of correlation in mean 50% inhibitory concentration (Pearson's r = 0.99, p = 0.0417). Of the seven patients, five patients (71.5%) had partial responses to erlotinib 25 mg/d. Median progression-free survival was 17 months (95% confidence interval, 6-35 months). Toxicities were minimal, with only two (28.5%) patients having a rash and none experiencing (0%) diarrhea. In NSCLC cell lines, gefitinib and erlotinib have similar inhibitory profiles. In patients with NSCLC and EGFR-activating mutations, a dose of erlotinib 25 mg/d (equivalent to gefitinib 250 mg/d) leads to impressive response rates and progression-free survival similar to the growing experience with the approved doses of gefitinib (250 mg/d) and erlotinib (150 mg/d). Identifying prospectively the lowest and clinically active dose ranges of erlotinib and gefitinib will help further to personalize care for patients with tumors harboring EGFR mutations.
International Journal of Radiation Oncology*Biology*Physics, 2014
Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastas... more Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole brain RT (WBRT), and 15 with stereotactic radiosurgery (SRS). The median overall survival (OS) for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median, 35 vs 26 months; P=.62), whereas patients treated with SRS had a longer OS than did those in the erlotinib group (median, 64 months; P=.004). The median time to intracranial progression was 17 months. There was a longer time to intracranial progression in patients who received WBRT than in those who received erlotinib upfront (median, 24 vs 16 months, P=.04). Patients in the erlotinib or SRS group were more likely to experience intracranial failure as a component of first failure, whereas WBRT patients were more likely to experience failure outside the brain (P=.004). The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system activity.
Journal of the National Comprehensive Cancer Network : JNCCN, 2015
These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small ... more These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 13, 2015
AUY922 is an HSP90 inhibitor that causes degradation of HSP chaperones and their client proteins,... more AUY922 is an HSP90 inhibitor that causes degradation of HSP chaperones and their client proteins, including epidermal growth factor receptor. We conducted a phase I/II trial to evaluate AUY922 and erlotinib for patients with EGFR-mutant lung cancer and disease progression during erlotinib treatment. All patients had developed acquired resistance after treatment with erlotinib and underwent repeat tumor biopsies before study entry to assess for EGFR T790M. In phase I, 18 patients were treated with AUY922 intravenously once per week and erlotinib once per day in 28-day cycles using a 3 + 3 dose-escalation design. In phase II, 19 additional patients were treated at the maximum-tolerated dose. The primary end point of the phase II trial was complete plus partial response rate. In phase I (n = 18), three patients were treated in each cohort, except the highest-dose cohort (AUY922 70 mg and erlotinib 150 mg), which expanded to six patients because of a dose-limiting toxicity (ie, junction...
Prognostic variables are independently associated with survival and are fundamental to clinical t... more Prognostic variables are independently associated with survival and are fundamental to clinical trial design. In the current study, the authors evaluated the impact of stage of disease at the time of the initial diagnosis on overall survival (OS) in 2 independent, oncogene-defined cohorts. All patients with epidermal growth factor receptor (EGFR)-mutant and KRAS-mutant metastatic lung adenocarcinomas were identified through routine molecular testing from January 2005 through January 2011. Clinical characteristics were obtained. OS from the date of diagnosis of recurrent or de novo metastatic disease was estimated using the Kaplan-Meier method. A total of 635 patients with KRAS-mutant and 496 patients with EGFR-mutant metastatic lung adenocarcinomas were identified. Among patients with KRAS-mutant lung adenocarcinomas, those with de novo metastatic disease were found to have a shorter median OS compared with those with recurrent metastatic disease (13 months vs 18 months; P = .003). ...
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting, 2012
Thymic carcinomas represent approximately 10% of thymic tumors. In our approach to patients with ... more Thymic carcinomas represent approximately 10% of thymic tumors. In our approach to patients with thymic carcinoma, we emphasize multimodality treatment with close communication between the pathologist, thoracic surgeon, medical oncologist, and radiation oncologist. Given the paucity of high-quality clinical research data, treatment decisions are guided by a small amount of prospective trial data, retrospective reports, and clinical experience. Surgical management of thymic carcinoma must account for the more aggressive biology, higher degree of local invasion of neighboring structures, greater propensity for nodal metastasis, and higher risk of distant metastatic disease. Although surgical resection remains the most important component in the management of localized thymic tumors, radiation therapy (RT) may be used as adjuvant therapy after surgical resection or as the definitive treatment modality in patients who are deemed unresectable because of medical comorbidities or technical...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2006
In 2004, several investigators reported that somatic mutations in the epidermal growth factor rec... more In 2004, several investigators reported that somatic mutations in the epidermal growth factor receptor gene were associated with clinical responses to erlotinib and gefitinib in patients with non-small cell lung cancer. Since then, multiple groups have examined the biological properties that such mutations confer as well as the clinical relevance of these mutations in patients with non-small cell lung cancer. Although a tremendous amount of knowledge has been gained in the past 2 years, there remain a number of important epidemiologic, biological, and clinical questions.
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Papers by Gregory Riely