This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Background: Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese pa... more Background: Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese patients with completely resected, p-stage I (T1> 2 cm) non-small cell lung cancer (NSCLC). This trial, the Japan Clinical Oncology Group (JCOG) 0707, aimed at estimating the efficacy of S-1 (tegafur/gimeracil/oteracil) compared to UFT as adjuvant therapy in this population. Method: Eligible patients had received complete resection with lymph node dissection for p-stage I (T1-2N0M0, T1> 2 cm, by 5 th Edition UICC TNM) NSCLC, within 56 days of enrollment. Patients were randomized to receive: oral UFT 250mg/m 2 /day for 2 years (Arm A), or oral S-1 80mg/m 2 /day for 2 weeks and 1 week rest, for 1 year (Arm B). The initial primary endpoint was overall survival (OS). Based upon the monitoring in Jun. 2013, which showed the combined OS of the 2 arms better than expected (4-year OS of 91.6% vs. presumed 5-year OS of 70-76.5%), it was judged to be underpowered. The study protocol was amended so that the primary endpoint is relapse-free survival (RFS). With the calculated sample size of 960, this study would detect the superiority of Arm B over Arm A with power 80% and one-sided type I error of 0.05, assuming the 5-year RFS of 75% in Arm A and the hazard ratio of 0.75. Result: From Nov. 2008 to Dec. 2013, 963 patients were enrolled (Arm A: 482, Arm B : 481): median age 66 (range: 33 to 80), male 58%, adenocarcinoma 80%, p-T1/T2 46%/54%. Only 2 received pneumonectomy. Grade 3 toxicities (hematologic/nonhematologic) were observed in 15.9 (1.5/14.7) % in Arm A, and in 14.9 (3.6/12.1) % in Arm B, respectively. 60.0% of the patients in Arm A and 54.7% of them in Arm B completed the protocol treatment (p¼0.10). There were 4 cases of deaths during protocol treatment, probably of cardio-vascular origin, with 1 in Arm A and 3 in Arm B. At the data cutoff of Dec. 2018, the hazard ratio (HR, Arm B vs. Arm A) of RFS was 1.06 (95% confidence interval (C.I.): 0.82-1.36), showing no superiority of S-1 over UFT. The HR of OS was 1.10 (95% C.I.: 0.81-1.50). The 5-year RFS/OS rates were 79.4%/88.8% in Arm A and 79.5%/89.7% in Arm B, respectively. Pre-specified subset analyses for gender, age, smoking, stage, tumor side, lymph node dissection area, pleural invasion and histology revealed no remarkable results; S-1 arm was not superior to UFT arm in each analysis. Of the 77 and 85 OS events for Arm A/Arm B, 45 each (58%/53%, respectively) were due to the NSCLC. During the follow-up period, secondary malignancy was observed in 85 (17.8%) and 84 (17.8%) in Arm A and Arm B, respectively. Conclusion: Post-operative adjuvant therapy with oral S-1 was not superior to that with UFT in stage I (T>2 cm) NSCLC after complete resection. UFT remains standard in this population. Future investigation should incorporate identification of high-risk population for recurrence, since survival of each arm was so good with substantial number of OS events due to other causes of deaths in this trial.
Background: Upregulated expression and aberrant activation of the epidermal growth-factor recepto... more Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of !200) and/or gene copy numbers of EGFR (e.g. !40% cells with !4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in !10% of analyzed cells) derive greater therapeutic benefits from EGFRdirected mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.
Background Ceritinib is approved for the treatment of pts with metastatic ALK+ NSCLC. In previous... more Background Ceritinib is approved for the treatment of pts with metastatic ALK+ NSCLC. In previous studies (ASCEND-1 to 5), ceritinib was highly active in ALK+ NSCLC pts with reported intracranial responses in pts with measurable baseline brain lesions. ASCEND-7 (NCT02336451) was designed to specifically study intracranial effects of ceritinib and we report here efficacy and safety in pts with ALK+ NSCLC metastatic to the brain (Arms 1-4). Methods Eligible pts had, WHO performance status 0-2, ALK + (FISH) NSCLC, with active brain metastases (BM) either newly diagnosed or progressive, and ≥1 extracranial measurable lesion using RECIST v1.1. Pts may have been pretreated with chemotherapy and/or crizotinib (ALK inhibitor [ALKi]). Pts were assigned to arms 1 to 4 depending on prior treatment (refer to below table). Primary endpoint was investigator assessed whole body overall response rate (CR or PR) and key secondary endpoint was investigator assessed disease control rate (CR or PR or S...
NSCLC. However, EGFR-TKIs might alter this status. We sought to compare the prevalence of T790M u... more NSCLC. However, EGFR-TKIs might alter this status. We sought to compare the prevalence of T790M upon acquired resistance to EGFR-TKIs between 19del and L858R by assembling all existed data. Method: Electronic databases were comprehensively searched for eligible studies. The primary endpoint was the odds ratio (OR) of T790M mutation in NSCLC co-existing with L858R mutation and 19del upon resistance to first-generation EGFR-TKIs. A random effects model was used. Stratified analysis was performed based on study type (retrospective and prospective), race (Asians and Caucasians) and sample type (tissue and plasma). Result: A total of 25 studies involving 1,770 patients were included. The overall T790M existent rate was 45.25%. Post-resistance T790M was more frequent in 19del than in L858R mutated patients (53% vs. 36%; OR 1.87; p¼0.00). All outcomes of subgroup and overall analyses were similar. In contrast, we re-analyzed the previous meta-analysis, finding that the pooled rate of pretreatment T790M was 14% and 22% in 19del and L858R respectively (OR 0.59; p<0.01). The increase of T790M rate was 2.79-fold in 19del and only 0.63-fold in L858R in the course of EGFR-TKIs therapy. Conclusion: Opposite to the situation of de novo T790M, it was observed that T790M was more frequent in exon 19del than in L858R among EGFR-TKI resistant acquired patients. The difference in T790M alteration between 19del and L858R encourages development of specific resistance mechanism detection or treatment strategies.
Median follow-up exceeded 15 months. Median and landmark OS (1year, 18-months, 2-year) and DoT in... more Median follow-up exceeded 15 months. Median and landmark OS (1year, 18-months, 2-year) and DoT including data for a subset of 3L patients, matched for I/E criteria to CheckMate 032 (n¼92), are reported in the table. Conclusion: Poor survival among US patients treated for 3L SCLC emphasizes the need for more effective and tolerable therapies. In CheckMate 032, nivolumab demonstrated considerable activity in heavily pretreated patients when compared to real-world data and may represent a therapeutic option over available treatments.
of cycles: 11 (1-68). Most were current or former smokers (94,6%). Only 2,3% had EGFR mutations, ... more of cycles: 11 (1-68). Most were current or former smokers (94,6%). Only 2,3% had EGFR mutations, and 0,6% ALK rearrangement. PD-L1 immunohistochemistry was only available in 25% of patients (<1%: 36,6%; 1-49%: 39%; >¼50%: 24,4%). After calculating LIPI score, 56,4% were LIPI 0 (good prognosis), 38,5% LIPI 1 (intermediate prognosis), and 5,1% LIPI 2 (poor prognosis). Response rate (RR) was 30,4% and disease control rate (DCR) 52%. The median PFS and OS were 5,6 months (m) (3,9-7,3) and 11,4 m (9,4-13,5). Median OS for good, intermediate, and poor was 14m (95% CI, 11,2-16,7), 6,3m (95% CI, 0,6-12) and 1,8m (95% CI, 0-4,3), respectively (p¼0,0001). LIPI showed correlation with OS in patients with known PD-L1 status and also in those with no information about it. PFS was also correlated (p¼0,004) with LIPI score. A LIPI score of 2 was independently associated with poorer OS (HR 4,9; 95% CI, 2,18-11,1). Conclusion: Our results support the prognostic value of pretreatment LIPI score. dNLR >3 and LDH greater than ULN was correlated with worse outcomes for ICI, regardless of the knowledge of PD-L1 status. This is a useful tool, based on clinical criteria, that can help us in daily practice to identify which patients benefit from ICI.
tested PD-L1 <1%) has not been reached. Conclusion: Pegilodecakin, when added to anti-PD-1 therap... more tested PD-L1 <1%) has not been reached. Conclusion: Pegilodecakin, when added to anti-PD-1 therapy in advanced NSCLC patients, was associated with response rates and durability of benefit greater than has been seen with anti-PD-1 alone. Responses were seen in settings in which anti-PD-1 therapy has demonstrated limited benefit, such as absent PD-L1 expression, low TMB, and/or the presence of liver metastasis. These preliminary findings support further studies of pegilodecakin with anti-PD-1 therapies.
2099 Background: SNS-595 is a novel naphthyridine analog that induces a G2 cell cycle arrest in v... more 2099 Background: SNS-595 is a novel naphthyridine analog that induces a G2 cell cycle arrest in vitro and shows broad activity in xenograft and drug resistant tumor models. Methods: SNS-595 was administered to patients (pts) with advanced solid cancers every 3 weeks as an IV infusion over 10 minutes without premedications. Cohorts of 3–6 pts were accrued to doses based on a modified Fibonacci sequence. Results: As of 12/04 16 patients were treated in the first five cohorts at doses starting at 3 mg/m2 and advancing to 48 mg/m2. Tumor types included lung (4), adenocarcinoma of unknown primary (4), renal (3), ovarian, melanoma, bladder, sarcoma and cholangiocarcinoma (1 each). The median age was 57 years (range 46 to 74) and median ECOG PS was 1 (range 0–2). No dose limiting toxicity has been seen. Transient Grade 4 hematological toxicity (ANC <500/μL) was seen in 2 of 3 pts in cohort 5 (48 mg/m2). Non-hematologic toxicities were mild and all grade 1/2. PK samples were collected on treatment Day 1 and were ...
CRA1500 Background: Sex differences in lung cancer outcome suggest a potential hormonal influence... more CRA1500 Background: Sex differences in lung cancer outcome suggest a potential hormonal influence; however, observational studies provide mixed findings regarding menopausal hormone therapy (HT) and lung cancer. Methods: Secondary analyses of the WHI randomized, placebo-controlled trial of daily conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) in 16,608 multi-ethnic postmenopausal women, aged 50–79 were conducted on lung cancer incidence and mortality. Lung cancers were confirmed by medical record review. Results: Groups were balanced for age, race/ethnicity, and prior HT. Smoking status was also comparable (never 50%, past 40%, current 10% in both groups). Cumulative risk for lung cancer was highest in current (0.51%), compared to past (0.14%) and never (0.04%) smokers. After 5.6 years on trial intervention and 2.4 years additional follow-up (median), small cell lung cancer incidence was comparable between randomization groups (total n=26), as was subsequent small cell lung cancer mortality. Although a trend for more non-small cell lung cancer (NSCLC) diagnoses in the active hormone group was not significant (p=0.12), an apparent divergence emerged after five years, with more diagnoses in the CEE+MPA group. In addition, mortality after NSCLC diagnosis was significantly higher for the CEE+MPA group (46.3% vs 27.0%, respectively, hazard ratio (HR) 1.59, 95% CI 1.03–2.46, p=0.04). As a result, CEE+MPA group women were more likely to die from NSCLC than those on placebo (p=0.02). Conclusions: Use of CEE + MPA for over 5 years increases a woman's risk for NSCLC mortality, the leading cause of cancer death in women. These data, together with recent results indicating higher breast cancer risk (Cancer Res 2009;69(2):78s), suggest cancer impact should influence risk-to-benefit consideration for combined HT use. [Table: see text] [Table: see text]
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Background: Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese pa... more Background: Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese patients with completely resected, p-stage I (T1> 2 cm) non-small cell lung cancer (NSCLC). This trial, the Japan Clinical Oncology Group (JCOG) 0707, aimed at estimating the efficacy of S-1 (tegafur/gimeracil/oteracil) compared to UFT as adjuvant therapy in this population. Method: Eligible patients had received complete resection with lymph node dissection for p-stage I (T1-2N0M0, T1> 2 cm, by 5 th Edition UICC TNM) NSCLC, within 56 days of enrollment. Patients were randomized to receive: oral UFT 250mg/m 2 /day for 2 years (Arm A), or oral S-1 80mg/m 2 /day for 2 weeks and 1 week rest, for 1 year (Arm B). The initial primary endpoint was overall survival (OS). Based upon the monitoring in Jun. 2013, which showed the combined OS of the 2 arms better than expected (4-year OS of 91.6% vs. presumed 5-year OS of 70-76.5%), it was judged to be underpowered. The study protocol was amended so that the primary endpoint is relapse-free survival (RFS). With the calculated sample size of 960, this study would detect the superiority of Arm B over Arm A with power 80% and one-sided type I error of 0.05, assuming the 5-year RFS of 75% in Arm A and the hazard ratio of 0.75. Result: From Nov. 2008 to Dec. 2013, 963 patients were enrolled (Arm A: 482, Arm B : 481): median age 66 (range: 33 to 80), male 58%, adenocarcinoma 80%, p-T1/T2 46%/54%. Only 2 received pneumonectomy. Grade 3 toxicities (hematologic/nonhematologic) were observed in 15.9 (1.5/14.7) % in Arm A, and in 14.9 (3.6/12.1) % in Arm B, respectively. 60.0% of the patients in Arm A and 54.7% of them in Arm B completed the protocol treatment (p¼0.10). There were 4 cases of deaths during protocol treatment, probably of cardio-vascular origin, with 1 in Arm A and 3 in Arm B. At the data cutoff of Dec. 2018, the hazard ratio (HR, Arm B vs. Arm A) of RFS was 1.06 (95% confidence interval (C.I.): 0.82-1.36), showing no superiority of S-1 over UFT. The HR of OS was 1.10 (95% C.I.: 0.81-1.50). The 5-year RFS/OS rates were 79.4%/88.8% in Arm A and 79.5%/89.7% in Arm B, respectively. Pre-specified subset analyses for gender, age, smoking, stage, tumor side, lymph node dissection area, pleural invasion and histology revealed no remarkable results; S-1 arm was not superior to UFT arm in each analysis. Of the 77 and 85 OS events for Arm A/Arm B, 45 each (58%/53%, respectively) were due to the NSCLC. During the follow-up period, secondary malignancy was observed in 85 (17.8%) and 84 (17.8%) in Arm A and Arm B, respectively. Conclusion: Post-operative adjuvant therapy with oral S-1 was not superior to that with UFT in stage I (T>2 cm) NSCLC after complete resection. UFT remains standard in this population. Future investigation should incorporate identification of high-risk population for recurrence, since survival of each arm was so good with substantial number of OS events due to other causes of deaths in this trial.
Background: Upregulated expression and aberrant activation of the epidermal growth-factor recepto... more Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of !200) and/or gene copy numbers of EGFR (e.g. !40% cells with !4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in !10% of analyzed cells) derive greater therapeutic benefits from EGFRdirected mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.
Background Ceritinib is approved for the treatment of pts with metastatic ALK+ NSCLC. In previous... more Background Ceritinib is approved for the treatment of pts with metastatic ALK+ NSCLC. In previous studies (ASCEND-1 to 5), ceritinib was highly active in ALK+ NSCLC pts with reported intracranial responses in pts with measurable baseline brain lesions. ASCEND-7 (NCT02336451) was designed to specifically study intracranial effects of ceritinib and we report here efficacy and safety in pts with ALK+ NSCLC metastatic to the brain (Arms 1-4). Methods Eligible pts had, WHO performance status 0-2, ALK + (FISH) NSCLC, with active brain metastases (BM) either newly diagnosed or progressive, and ≥1 extracranial measurable lesion using RECIST v1.1. Pts may have been pretreated with chemotherapy and/or crizotinib (ALK inhibitor [ALKi]). Pts were assigned to arms 1 to 4 depending on prior treatment (refer to below table). Primary endpoint was investigator assessed whole body overall response rate (CR or PR) and key secondary endpoint was investigator assessed disease control rate (CR or PR or S...
NSCLC. However, EGFR-TKIs might alter this status. We sought to compare the prevalence of T790M u... more NSCLC. However, EGFR-TKIs might alter this status. We sought to compare the prevalence of T790M upon acquired resistance to EGFR-TKIs between 19del and L858R by assembling all existed data. Method: Electronic databases were comprehensively searched for eligible studies. The primary endpoint was the odds ratio (OR) of T790M mutation in NSCLC co-existing with L858R mutation and 19del upon resistance to first-generation EGFR-TKIs. A random effects model was used. Stratified analysis was performed based on study type (retrospective and prospective), race (Asians and Caucasians) and sample type (tissue and plasma). Result: A total of 25 studies involving 1,770 patients were included. The overall T790M existent rate was 45.25%. Post-resistance T790M was more frequent in 19del than in L858R mutated patients (53% vs. 36%; OR 1.87; p¼0.00). All outcomes of subgroup and overall analyses were similar. In contrast, we re-analyzed the previous meta-analysis, finding that the pooled rate of pretreatment T790M was 14% and 22% in 19del and L858R respectively (OR 0.59; p<0.01). The increase of T790M rate was 2.79-fold in 19del and only 0.63-fold in L858R in the course of EGFR-TKIs therapy. Conclusion: Opposite to the situation of de novo T790M, it was observed that T790M was more frequent in exon 19del than in L858R among EGFR-TKI resistant acquired patients. The difference in T790M alteration between 19del and L858R encourages development of specific resistance mechanism detection or treatment strategies.
Median follow-up exceeded 15 months. Median and landmark OS (1year, 18-months, 2-year) and DoT in... more Median follow-up exceeded 15 months. Median and landmark OS (1year, 18-months, 2-year) and DoT including data for a subset of 3L patients, matched for I/E criteria to CheckMate 032 (n¼92), are reported in the table. Conclusion: Poor survival among US patients treated for 3L SCLC emphasizes the need for more effective and tolerable therapies. In CheckMate 032, nivolumab demonstrated considerable activity in heavily pretreated patients when compared to real-world data and may represent a therapeutic option over available treatments.
of cycles: 11 (1-68). Most were current or former smokers (94,6%). Only 2,3% had EGFR mutations, ... more of cycles: 11 (1-68). Most were current or former smokers (94,6%). Only 2,3% had EGFR mutations, and 0,6% ALK rearrangement. PD-L1 immunohistochemistry was only available in 25% of patients (<1%: 36,6%; 1-49%: 39%; >¼50%: 24,4%). After calculating LIPI score, 56,4% were LIPI 0 (good prognosis), 38,5% LIPI 1 (intermediate prognosis), and 5,1% LIPI 2 (poor prognosis). Response rate (RR) was 30,4% and disease control rate (DCR) 52%. The median PFS and OS were 5,6 months (m) (3,9-7,3) and 11,4 m (9,4-13,5). Median OS for good, intermediate, and poor was 14m (95% CI, 11,2-16,7), 6,3m (95% CI, 0,6-12) and 1,8m (95% CI, 0-4,3), respectively (p¼0,0001). LIPI showed correlation with OS in patients with known PD-L1 status and also in those with no information about it. PFS was also correlated (p¼0,004) with LIPI score. A LIPI score of 2 was independently associated with poorer OS (HR 4,9; 95% CI, 2,18-11,1). Conclusion: Our results support the prognostic value of pretreatment LIPI score. dNLR >3 and LDH greater than ULN was correlated with worse outcomes for ICI, regardless of the knowledge of PD-L1 status. This is a useful tool, based on clinical criteria, that can help us in daily practice to identify which patients benefit from ICI.
tested PD-L1 <1%) has not been reached. Conclusion: Pegilodecakin, when added to anti-PD-1 therap... more tested PD-L1 <1%) has not been reached. Conclusion: Pegilodecakin, when added to anti-PD-1 therapy in advanced NSCLC patients, was associated with response rates and durability of benefit greater than has been seen with anti-PD-1 alone. Responses were seen in settings in which anti-PD-1 therapy has demonstrated limited benefit, such as absent PD-L1 expression, low TMB, and/or the presence of liver metastasis. These preliminary findings support further studies of pegilodecakin with anti-PD-1 therapies.
2099 Background: SNS-595 is a novel naphthyridine analog that induces a G2 cell cycle arrest in v... more 2099 Background: SNS-595 is a novel naphthyridine analog that induces a G2 cell cycle arrest in vitro and shows broad activity in xenograft and drug resistant tumor models. Methods: SNS-595 was administered to patients (pts) with advanced solid cancers every 3 weeks as an IV infusion over 10 minutes without premedications. Cohorts of 3–6 pts were accrued to doses based on a modified Fibonacci sequence. Results: As of 12/04 16 patients were treated in the first five cohorts at doses starting at 3 mg/m2 and advancing to 48 mg/m2. Tumor types included lung (4), adenocarcinoma of unknown primary (4), renal (3), ovarian, melanoma, bladder, sarcoma and cholangiocarcinoma (1 each). The median age was 57 years (range 46 to 74) and median ECOG PS was 1 (range 0–2). No dose limiting toxicity has been seen. Transient Grade 4 hematological toxicity (ANC <500/μL) was seen in 2 of 3 pts in cohort 5 (48 mg/m2). Non-hematologic toxicities were mild and all grade 1/2. PK samples were collected on treatment Day 1 and were ...
CRA1500 Background: Sex differences in lung cancer outcome suggest a potential hormonal influence... more CRA1500 Background: Sex differences in lung cancer outcome suggest a potential hormonal influence; however, observational studies provide mixed findings regarding menopausal hormone therapy (HT) and lung cancer. Methods: Secondary analyses of the WHI randomized, placebo-controlled trial of daily conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) in 16,608 multi-ethnic postmenopausal women, aged 50–79 were conducted on lung cancer incidence and mortality. Lung cancers were confirmed by medical record review. Results: Groups were balanced for age, race/ethnicity, and prior HT. Smoking status was also comparable (never 50%, past 40%, current 10% in both groups). Cumulative risk for lung cancer was highest in current (0.51%), compared to past (0.14%) and never (0.04%) smokers. After 5.6 years on trial intervention and 2.4 years additional follow-up (median), small cell lung cancer incidence was comparable between randomization groups (total n=26), as was subsequent small cell lung cancer mortality. Although a trend for more non-small cell lung cancer (NSCLC) diagnoses in the active hormone group was not significant (p=0.12), an apparent divergence emerged after five years, with more diagnoses in the CEE+MPA group. In addition, mortality after NSCLC diagnosis was significantly higher for the CEE+MPA group (46.3% vs 27.0%, respectively, hazard ratio (HR) 1.59, 95% CI 1.03–2.46, p=0.04). As a result, CEE+MPA group women were more likely to die from NSCLC than those on placebo (p=0.02). Conclusions: Use of CEE + MPA for over 5 years increases a woman's risk for NSCLC mortality, the leading cause of cancer death in women. These data, together with recent results indicating higher breast cancer risk (Cancer Res 2009;69(2):78s), suggest cancer impact should influence risk-to-benefit consideration for combined HT use. [Table: see text] [Table: see text]
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