Publications by authors named "D Ross Camidge"

270 Publications

Evolution of MET and NRAS gene amplification as acquired resistance mechanisms in EGFR mutant NSCLC.

NPJ Precis Oncol 2021 Oct 12;5(1):91. Epub 2021 Oct 12.

Department of Medicine, Division of Medical Oncology, University of Colorado- Anschutz Medical Campus, Aurora, CO, USA.

EGFR mutant non-small cell lung cancer patients' disease demonstrates remarkable responses to EGFR-targeted therapy, but inevitably they succumb to acquired resistance, which can be complex and difficult to treat. Analyzing acquired resistance through broad molecular testing is crucial to understanding the resistance mechanisms and developing new treatment options. We performed diverse clinical testing on a patient with successive stages of acquired resistance, first to an EGFR inhibitor with MET gene amplification and then subsequently to a combination EGFR and MET targeted therapies. A patient-derived cell line obtained at the time of disease progression was used to identify NRAS gene amplification as an additional driver of drug resistance to combination EGFR/MET therapies. Analysis of downstream signaling revealed extracellular signal-related kinase activation that could only be eliminated by trametinib treatment, while Akt activation could be modulated by various combinations of MET, EGFR, and PI3K inhibitors. The combination of an EGFR inhibitor with a MEK inhibitor was identified as a possible treatment option to overcome drug resistance related to NRAS gene amplification.
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http://dx.doi.org/10.1038/s41698-021-00231-xDOI Listing
October 2021

Free-Living Energy Balance Behaviors Are Associated With Greater Weight Loss During a Weight Loss Program.

Front Nutr 2021 14;8:688295. Epub 2021 Sep 14.

Department of Psychology, University of Sheffield, Sheffield, United Kingdom.

Free-living movement (physical activity [PA] and sedentary behavior [SB]) and eating behaviors (energy intake [EI] and food choice) affect energy balance and therefore have the potential to influence weight loss (WL). This study explored whether free-living movement and/or eating behaviors measured early (week 3) in a 14-week WL programme or their change during the intervention are associated with WL in women. In the study, 80 women ( ± age: 42.0 ± 12.4 years) with overweight or obesity [body mass index (BMI): 34.08 ± 3.62 kg/m] completed a 14 week WL program focused primarily on diet (commercial or self-led). Body mass (BM) was measured at baseline, and again during week 2 and 14 along with body composition. Free-living movement (SenseWear Armband) and eating behavior (weighed food diaries) were measured for 1 week during week 3 and 12. Hierarchical multiple regression analyses examined whether early and early-late change in free-living movement and eating behavior were associated with WL. The differences in behavior between clinically significant weight losers (CWL; ≥5% WL) and non-clinically significant weight losers (NWL; ≤ 3% WL) were compared. The energy density of food consumed [β = 0.45, < 0.001] and vigorous PA [β = -0.30, < 0.001] early in the intervention (regression model 1) and early-late change in light PA [β = -0.81 < 0.001], moderate PA [β = -1.17 < 0.001], vigorous PA [β = -0.49, < 0.001], total energy expenditure (EE) [β = 1.84, < 0.001], and energy density of food consumed [β = 0.27, = 0.01] (regression model 2) significantly predicted percentage change in BM. Early in the intervention, CWL consumed less energy dense foods than NWL [ = 0.03]. CWL showed a small but significant increase in vigorous PA, whereas NWL showed a slight decrease in PA [ = 0.04]. Both early and early-late change in free-living movement and eating behaviors during a 14 week WL program are predictors of WL. These findings demonstrate that specific behaviors that contribute to greater EE (e.g., vigorous PA) and lower EI (e.g., less energy-dense foods) are related to greater WL outcomes. Interventions targeting these behaviors can be expected to increase the effectiveness of WL programs.
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http://dx.doi.org/10.3389/fnut.2021.688295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478016PMC
September 2021

Brigatinib Versus Crizotinib in ALK Inhibitor-Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial.

J Thorac Oncol 2021 Sep 16. Epub 2021 Sep 16.

Royal Marsden Hospital, London, United Kingdom.

Introduction: In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor-naive advanced ALK-positive NSCLC, brigatinib exhibited superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results.

Methods: Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee-assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy.

Results: A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35-0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53-1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21-0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed.

Conclusions: In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study.
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http://dx.doi.org/10.1016/j.jtho.2021.07.035DOI Listing
September 2021

Cost-effectiveness of nivolumab monotherapy in the third-line treatment of small cell lung cancer.

J Med Econ 2021 Jan-Dec;24(1):1124-1133

Worldwide Health Economics & Outcomes Research, Bristol Myers Squibb, Princeton, NJ, USA.

Aims: Present cost-effectiveness analysis of nivolumab monotherapy vs. commonly prescribed third-line (3 L+) treatment in small cell lung cancer (SCLC).

Materials And Methods: A three health states partitioned survival model (progression-free, progressed disease, and death; US payer perspective) was developed. The systematic literature review identified no randomized controlled or single-arm trials with separate outcomes for 3 L + SCLC patients. Topotecan was chosen as a comparator because it is frequently prescribed in real-world practice for 3 L SCLC. Clinical inputs for topotecan were derived from the Flatiron database with inclusion/exclusion criteria matched to patients treated with 3 L + nivolumab in CheckMate 032. Intravenous (IV) and oral topotecan clinical efficacy were assumed equivalent. Base-case analysis used a 20-year lifetime horizon. An annual discount rate of 3.0% for costs and outcomes was applied. Uncertainty was assessed using sensitivity analyses adjusted for key parameters.

Results: Incremental cost per quality-adjusted life-year (QALY) gained with nivolumab was US$153,312 vs. IV topotecan and US$123,003 vs. oral topotecan, respectively. When results were disaggregated, nivolumab-related costs were mainly driven by drug acquisition costs, and topotecan-related costs were primarily due to adverse event treatment. Mean overall survival (OS) was 21.69 months with nivolumab and 5.80 months with IV or oral topotecan. More favorable outcomes were found by the landmark response analyses. Deterministic sensitivity analyses showed that changes to the discount rate for costs and outcomes and body weight had the greatest impacts on results.

Limitations: Included use of real-world data for OS outcomes associated with 3 L topotecan, use of second-line topotecan data for progression-free survival, and no indirect costs.

Conclusions: Based on the literature on willingness-to-pay for a QALY in metastatic cancer, nivolumab monotherapy might represent a cost-effective option for 3 L + treatment of SCLC compared with IV and oral topotecan. Sensitivity analysis using response-based methods yielded further favorable cost-effectiveness estimates.
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http://dx.doi.org/10.1080/13696998.2021.1974763DOI Listing
October 2021

Brain Metastases in EGFR- and ALK-Positive NSCLC: Outcomes of Central Nervous System-Penetrant Tyrosine Kinase Inhibitors Alone Versus in Combination With Radiation.

J Thorac Oncol 2021 Aug 26. Epub 2021 Aug 26.

Division of Medical Oncology, UCSF Helen Diller Comprehensive Cancer Center, San Francisco, California; Currently employed by Genentech Inc., South San Francisco, California. Electronic address:

Introduction: Management of central nervous system (CNS) metastases in patients with driver-mutated NSCLC has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases.

Methods: Data were retrospectively collected from three academic institutions. Two treatment groups (CNS-penetrant TKI alone versus TKI + CNS radiation therapy) were compared for both EGFR- and ALK-positive cohorts. Outcome variables included time to progression, time to intracranial progression, and time to treatment failure, measured from the date of initiation of CNS-penetrant TKI therapy.

Results: A total of 147 patients were included (EGFR n = 94, ALK n = 52, both n = 1). In patients receiving radiation, larger metastases, neurologic symptoms, and receipt of steroids were more common. There were no significant differences between TKI and CNS radiation therapy plus TKI groups for any of the study outcomes, including time to progression (8.5 versus 6.9 mo, p = 0.13 [EFGR] and 11.4 versus 13.4 mo, p = 0.98 [ALK]), time to intracranial progression (14.8 versus 20.5 mo, p = 0.51 [EGFR] and 18.1 versus 21.8 mo, p = 0.65 [ALK]), or time to treatment failure (13.8 versus 8.6 mo, p = 0.26 [EGFR] and 13.5 versus 23.2 mo, p = 0.95 [ALK]).

Conclusions: These results provide preliminary evidence that intracranial activity of CNS-penetrant TKIs may enable local radiation to be deferred in appropriately selected patients without negatively affecting progression.
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http://dx.doi.org/10.1016/j.jtho.2021.08.009DOI Listing
August 2021
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