Genomic characterization of thymic epithelial tumors in a real-world dataset.

BACKGROUND: Thymic epithelial tumors (TETs) are rare neoplasms arising in the mediastinum, including thymic carcinomas and thymomas. Due to their rarity, little is known about the genomic profiles of TETs. Herein, we investigated the genomic characteristics of TETs evaluated in a large comprehensive genomic profiling database in a real-world setting. METHODS: We included data from two different cohorts: Foundation Medicine Inc. (FMI) in the United States and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. Samples profiled were examined for all classes of alterations in 253 genes targeted across all assays. Tumor mutational burden (TMB) and microsatellite instability (MSI) were also evaluated. RESULTS: A total of 794 patients were collected in our study, including 722 cases from FMI and 72 cases from C-CAT. In the FMI data, CDKN2A (39.9%), TP53 (30.2%) and CDKN2B (24.6%) were frequently altered in thymic carcinoma, versus TP53 (7.8%), DNMT3A (6.8%), and CDKN2A (5.8%) in thymoma. TMB-high (≥10 mutations/Mb) and MSI were present in 7.0% and 2.3% of thymic carcinomas, and 1.6% and 0.3% of thymomas, respectively. Within C-CAT data, CDKN2A (38.5%), TP53 (36.5%) and CDKN2B (30.8%) were also frequently altered in thymic carcinoma, while alterations of TSC1, SETD2 and LTK (20.0% each) were found in thymoma. CONCLUSIONS: To the best of our knowledge, this is the largest cohort in which genomic alterations, TMB and MSI status of TETs were investigated. Potential targets for treatment previously unbeknownst in TETs are identified in this study, entailing newfound opportunities to advance therapeutic development.

Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial.

BACKGROUND: IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in the programmed death-ligand 1 (PD-L1)-positive and all stage II-IIIA non-small-cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are reported here. PATIENT AND METHODS: The design, participants, and primary-endpoint DFS outcomes have been reported for this phase III, open-label, 1 : 1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) versus BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (≥4 cm)-IIIA NSCLC (per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system, 7th edition). Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay). RESULTS: At a median of 45.3 months' follow-up on 18 April 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified hazard ratio (HR) was 0.995 [95% confidence interval (CI) 0.78-1.28]. The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n = 882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 tumour cell (TC) ≥1% (n = 476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC ≥50% (n = 229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis [grade 3/4 in 53 (10.7%) and grade 5 in 4 (0.8%) of 495 patients, respectively]. CONCLUSIONS: Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC ≥50% stage II-IIIA subgroup. No new safety signals were observed after 13 months' additional follow-up. Together, these findings support the positive benefit-risk profile of adjuvant atezolizumab in this setting.

Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.

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

Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer.

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 EGFR-directed 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.

Oral bisphosphonate use and lung cancer incidence among postmenopausal women.

Background: Bisphosphonates are common medications for the treatment of osteoporosis in older populations. Several studies, including the Women's Health Initiative (WHI), have found inverse associations of bisphosphonate use with risk of breast and endometrial cancer, but little is known about its association with other common malignancies. The objective of this study was to evaluate the association of bisphosphonate use on the incidence of lung cancer in the WHI. Patients and methods: The association between oral bisphosphonate use and lung cancer risk was examined in 151 432 postmenopausal women enrolled into the WHI in 1993-1998. At baseline and during follow-up, participants completed an inventory of regularly used medications including bisphosphonates. Results: After a mean follow-up of 13.3 years, 2511 women were diagnosed with incident lung cancer. There was no evidence of a difference in lung cancer incidence between oral bisphosphonate users and never users (adjusted hazard ratio = 0.91; 95% confidence intervals, 0.80-1.04; P = 0.16). However, an inverse association was observed among those who were never smokers (hazard ratio = 0.57, 95% confidence interval, 0.39-0.84; P < 0.01). Conclusion: In this large prospective cohort of postmenopausal women, oral bisphosphonate use was associated with significantly lower lung cancer risk among never smokers, suggesting bisphosphonates may have a protective effect against lung cancer. Additional studies are needed to confirm our findings.

Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma.

Background: A major limitation of circulating tumor DNA (ctDNA) for somatic mutation detection has been the low level of ctDNA found in a subset of cancer patients. We investigated whether using a combined isolation of exosomal RNA (exoRNA) and cell-free DNA (cfDNA) could improve blood-based liquid biopsy for EGFR mutation detection in non-small-cell lung cancer (NSCLC) patients. Patients and methods: Matched pretreatment tumor and plasma were collected from 84 patients enrolled in TIGER-X (NCT01526928), a phase 1/2 study of rociletinib in mutant EGFR NSCLC patients. The combined isolated exoRNA and cfDNA (exoNA) was analyzed blinded for mutations using a targeted next-generation sequencing panel (EXO1000) and compared with existing data from the same samples using analysis of ctDNA by BEAMing. Results: For exoNA, the sensitivity was 98% for detection of activating EGFR mutations and 90% for EGFR T790M. The corresponding sensitivities for ctDNA by BEAMing were 82% for activating mutations and 84% for T790M. In a subgroup of patients with intrathoracic metastatic disease (M0/M1a; n = 21), the sensitivity increased from 26% to 74% for activating mutations (P = 0.003) and from 19% to 31% for T790M (P = 0.5) when using exoNA for detection. Conclusions: Combining exoRNA and ctDNA increased the sensitivity for EGFR mutation detection in plasma, with the largest improvement seen in the subgroup of M0/M1a disease patients known to have low levels of ctDNA and poses challenges for mutation detection on ctDNA alone. Clinical Trials: NCT01526928.

Treatment, overall survival, and costs in patients with ALK-positive non-small-cell lung cancer after crizotinib monotherapy.

BACKGROUND: Limited post-crizotinib treatment options for ALK-positive non-small cell lung cancer (NSCLC) might lead to poor survival and high economic burden. OBJECTIVE: To evaluate real-world treatment patterns, overall survival (OS), and costs following crizotinib discontinuation. METHODS: This study used chart review and claims data. First, 27 participating US oncologists reviewed medical records of ALK-positive NSCLC patients who discontinued crizotinib monotherapy and reported patient demographic and clinical information, including post-crizotinib treatment and mortality. OS was estimated using Kaplan-Meier analyses. Second, three large administrative US claims databases were pooled. NSCLC patients were selected if they discontinued crizotinib monotherapy. Post-crizotinib costs were analyzed separately for patients who did or did not discontinue antineoplastic treatment after crizotinib monotherapy. All data were collected prior to ceritinib approval for this patient population. RESULTS: A total of 119 ALK-positive NSCLC patients discontinued crizotinib monotherapy. Upon discontinuation, 42% had no additional antineoplastic treatment and 13% received radiation therapy only. The median OS post-crizotinib was 61 days; patients with brain metastases had shorter OS than those who did not (44 vs. 69 days, P = 0.018), and patients without further antineoplastic treatment had shorter OS than those who did (17 vs. 180 days, P < 0.001). From claims data, 305 ALK-positive NSCLC patients discontinued crizotinib monotherapy. After discontinuation, 72% had no additional antineoplastic treatment. Among patients who continued antineoplastic treatment, monthly healthcare costs averaged $22,160, driven by pharmacy ($9202), inpatient ($6419), and outpatient radiotherapy ($2888) and imaging ($1179) costs. Among patients who discontinued any antineoplastic treatment, monthly healthcare costs averaged $3423, mostly driven by inpatient costs ($2074). CONCLUSIONS: After crizotinib monotherapy, most patients either received radiotherapy only or discontinued antineoplastic treatment altogether. OS after discontinuing crizotinib was poor and shorter among those with brain metastases than without, and among those without subsequent antineoplastic treatment than with. Patients who continued antineoplastic treatment incurred substantial healthcare costs.

Active and passive smoking in relation to lung cancer incidence in the Women's Health Initiative Observational Study prospective cohort.

BACKGROUND: Lung cancer is the leading cause of worldwide cancer deaths. While smoking is its leading risk factor, few prospective cohort studies have reported on the association of lung cancer with both active and passive smoking. This study aimed to determine the relationship between lung cancer incidence with both active and passive smoking (childhood, adult at home, and at work). PATIENTS AND METHODS: The Women's Health Initiative Observational Study (WHI-OS) was a prospective cohort study conducted at 40 US centers that enrolled postmenopausal women from 1993 to 1999. Among 93 676 multiethnic participants aged 50-79, 76 304 women with complete smoking and covariate data comprised the analytic cohort. Lung cancer incidence was calculated by Cox proportional hazards models, stratified by smoking status. RESULTS: Over 10.5 mean follow-up years, 901 lung cancer cases were identified. Compared with never smokers (NS), lung cancer incidence was much higher in current [hazard ratio (HR) 13.44, 95% confidence interval (CI) 10.80-16.75] and former smokers (FS; HR 4.20, 95% CI 3.48-5.08) in a dose-dependent manner. Current and FS had significantly increased risk for all lung cancer subtypes, particularly small-cell and squamous cell carcinoma. Among NS, any passive smoking exposure did not significantly increase lung cancer risk (HR 0.88, 95% CI 0.52-1.49). However, risk tended to be increased in NS with adult home passive smoking exposure ≥30 years, compared with NS with no adult home exposure (HR 1.61, 95% CI 1.00-2.58). CONCLUSIONS: In this prospective cohort of postmenopausal women, active smoking significantly increased risk of all lung cancer subtypes; current smokers had significantly increased risk compared with FS. Among NS, prolonged passive adult home exposure tended to increase lung cancer risk. These data support continued need for smoking prevention and cessation interventions, passive smoking research, and further study of lung cancer risk factors in addition to smoking. CLINICALTRIALS.GOV: NCT00000611.

A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer.

BACKGROUND: This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC). METHODS: This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients. RESULTS: The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months. CONCLUSION: Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.

A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours.

BACKGROUND: To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin. METHODS: Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations. RESULTS: Eighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ≥ 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted. CONCLUSION: The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.

Differential effect of age on survival in advanced NSCLC in women versus men: analysis of recent Eastern Cooperative Oncology Group (ECOG) studies, with and without bevacizumab.

BACKGROUND: The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex. PATIENTS AND METHODS: Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel ± bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of <60 or ≥60 years old. Eligible E4599 patients (N=850) were similarly separated by age and sex and by treatment (± bevacizumab). Survival was calculated separately for each cohort. RESULTS: The median survival time (MST) for women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women <60 (p=0.03). MST was 7.4 and 8.3 months for men ≥60 and <60 years old respectively (NS). In E4599 the age <60 by bevacizumab treatment interaction was statistically significant (p=0.03) for women (younger had greater benefit), with no age effect in men. CONCLUSIONS: In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599.

Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors.

BACKGROUND: Lexatumumab (HGS-ETR2) is a fully human agonistic mAb to the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 that activates the extrinsic apoptosis pathway and has potent preclinical antitumor activity. MATERIALS AND METHODS: This phase 1, dose escalation study assessed the safety, tolerability, pharmacokinetics (PKs) and immunogenicity of lexatumumab administered i.v. every 14 days in patients with advanced solid tumors. RESULTS: Thirty-one patients received lexatumumab over five dose levels (0.1-10 mg/kg). Most (26 of 31) received four or more cycles of treatment. One patient at 10 mg/kg experienced a possibly related dose-limiting toxicity of grade 3 hyperamylasemia. Nine patients achieved stable disease. One patient with chemotherapy-refractive Hodgkin's disease experienced a mixed response. Lexatumumab PKs were linear up to 10 mg/kg. At the 10 mg/kg dose, the mean (+/-standard deviation) t(1/2b) was 13.67 +/- 4.07 days, clearance was 4.95 +/- 1.93 ml/day/kg, V(1) was 45.55 ml/kg and V(ss) was 79.08 ml/kg, indicating that lexatumumab distributes outside the plasma compartment. No human antihuman antibodies were detected. CONCLUSIONS: Lexatumumab can be safely administered every 14 days at 10 mg/kg. The PK profile supports this schedule. Further evaluation of lexatumumab at this dose schedule is warranted, including combination trials with other agents.

Gemcitabine and pemetrexed administered in rapid sequence as front-line chemotherapy for advanced non-small-cell lung cancer: a phase II clinical trial.

BACKGROUND: Previous studies of the gemcitabine-pemetrexed combination in patients with late-stage non-small-cell lung cancer (NSCLC) utilized a 90-min delay between gemcitabine and pemetrexed administration. This phase II study evaluated activity when these agents were administered in rapid succession. MATERIALS AND METHODS: Chemonaive patients with late-stage NSCLC received gemcitabine 1250 mg/m(2) on days 1 and 8, with pemetrexed 500 mg/m(2) immediately following day 8 gemcitabine every 21 days for six cycles, folic acid, B(12), and steroid prophylaxis. RESULTS: Fifty-four enrolled patients (53 treated) completed a median of four cycles. Median dose intensity was 84% (gemcitabine) and 83% (pemetrexed); 68% of patients required dose adjustments. Response was as follows: complete response, 0; partial response, 7 (13%); stable disease, 29 (54%); progressive disease, 9 (17%); and unknown/unavailable, 9 (17%). Median progression-free and overall survival was 4.6 and 12.4 months, respectively. Common grade 3 or 4 toxic effects were as follows: neutropenia (40%); fatigue and dyspnea (21% each); pneumonia (17%); febrile neutropenia and thrombocytopenia (11% each); and anemia (6%). CONCLUSIONS: The gemcitabine-pemetrexed combination is minimally active in late-stage NSCLC, with a high incidence of grade 3 or 4 toxic effects requiring frequent dose adjustments. A gemcitabine dose <1250 mg/m(2) warrants consideration for future trials exploring this doublet. Administering day 8 pemetrexed immediately after gemcitabine does not appear to negatively impact therapeutic index.

Delta F508-CFTR channels: kinetics, activation by forskolin, and potentiation by xanthines.

Trafficking, activation, and kinetics of delta F508-cystic fibrosis transmembrane conductance regulator (CFTR) and CFTR were compared in stably transduced C127I mouse mammary epithelial cells. Western blots detected a small amount of fully glycosylated delta F508-CFTR Efflux of 125I was stimulated by forskolin with the same mean effective concentration (EC50; approximately 0.5 microM) for CFTR and delta F508-CFTR cells, but the maximum response was reduced more than fivefold and its latency increased approximately threefold in delta F508-CFTR cells. In delta F508-CFTR cells, 3-isobutyl-1-methylxanthine (IBMX; EC50 = 1.45 microM) and 8-cyclopentyl-1,3-dipropylxanthine (CPX; EC50 = 58 microM) increased the peak forskolin-stimulated efflux rate approximately 2.5-fold and decreased the time to peak. A sevenfold increase in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels accompanied potentiation of forskolin-induced 125I efflux by IBMX but not by CPX. Elevation of intracellular cAMP increased linear voltage-independent whole cell currents 30-fold in CFTR and 4-fold in delta F508-CFTR cells; the response rate in delta F508-CFTR cells was much slower. Single-channel currents were detected in 57 of 68 cell-attached patches from forskolin-prestimulated CFTR cells vs. 6 of 35 patches in delta F508-CFTR cells. Mean number of active channels per patch was 4.1 for CFTR [open probability (Po) = 0.34] and 0.2 for delta F508-CFTR (Po = 0.11). The lower Po of delta F508-CFTR resulted from an approximately threefold longer mean interburst interval. We estimate that forskolin-stimulated chloride conductance of delta F508-CFTR C127I cells is < 5% of CFTR cells. CPX is approximately 25-fold more potent than IBMX in potentiating delta F508-CFTR and may operate by a mechanism other than elevation of cAMP.