Michael Kelley

Overview:

1.     A major theme throughout my career has been the biology of and improving outcomes for patients with lung cancer.  Early publications examined the relationship between specific genetic alterations in lung cancer and clinically relevant applications including differential drug sensitivity, differentiation of metastases from second primary cancers, and application of patient-specific mutations as epitopes for immunotherapy.  Correlation of alteration of p16 with drug sensitivity led to identification of a class of CDK4 inhibitor. I served as the primary investigator or co-investigator in all of these studies.  I led a study that demonstrated that tubulin mutations are uncommon in lung cancer and described the artifactual detection of pseudogenes as the origin of a prior report claiming association of tubulin mutation with taxane sensitivity, thus correcting the scientific record. 

2.   A second area of continuing interest in lung cancer is the conduct of therapeutic and prevention clinical trials.  These trials have primarily been translation of hypotheses derived primarily from laboratory-based biological observations including the GRP autocrine growth factor in small cell lung cancer, a phase I study of a pulmonary toxin in non-small cell lung cancer, mutation-specific immunotherapy, and a putative chemopreventive agent for smokers.  More recently, I have been an active member of the Respiratory Committee of CALGB/Alliance including serving as principal investigator on a trial testing the addition of irinotecan to treatment of patients with small cell lung cancer. 

3.  Through my clinical practice, I identified a large family with the May-Hegglin anomaly, an autosomal dominant platelet condition characterized as thrombocytopenia, leukocyte inclusions, and giant platelets.  While the condition had been described in the early 1900s, the genetic basis was unknown.  I conceptualized and led a project to identify the underlying molecular basis of this frequently misdiagnosed disorder through classical genetics.  I then extended that observation to related genetic conditions (now known as MYH9-assocaited disorders) characterized by varying degrees of hematological abnormalities, hearing loss and renal disease.  Analysis of the spectrum of observed mutations and phenotypes resulted in identification of a genotype-phenotype association for the most medically significant aspects of the disorders.  Working with Dan Kiehart’s lab, we described the effect of commonly observed mutations of MYH9 on assembly of non-muscle myosin.  An animal model of the most common MYH9 mutation was created in my lab and demonstrated hematological abnormalities similar to those found in humans. 

4.  I described genetic linkage for a rare familial cancer syndrome characterized by very high penetrance of chordoma.  Subsequent linkage analysis resolved a phenotype mis-assignment and resulted in identification of germline gene duplication of the T-box gene, Brachyury in about half of affected families.  I then confirmed another groups report that a common coding region SNP of the Brachyury gene as well as additional genetic variants are associated with an increased risk for development of chordoma independent of amplification of the Brachyury gen.   To study the biology of chordoma, I established the origin of existing putative chordoma cell lines and working criteria for identification of possible new chordoma cell lines.  Using two confirmed chordoma cell lines, I screened all regulatory-approved drugs for anti-growth activity to determine whether any could be repurposed for clinical use in patients. 

5.  Beginning in 2007, I began to transition my career to a leadership position within the Department of Veterans Affairs as the National Program Director for Oncology.  This led to opportunities to utilize the vast and detailed clinical data sets of nearly 1 million patients with cancer to address questions that have been difficult to study either through randomized trials or in less robust datasets.  The use of surgery to treat early stage non-small cell lung cancer is a standard treatment for which I observed a racial disparity.  The lower rate of use of surgery among African Americans was not explained by association with comorbidity.  In another study, I described the rate of use of adjuvant chemotherapy as having increased temporally after publication of randomized trials showing a modest benefit to its use.  I showed that initially this chemotherapy was primarily carboplatin-based, despite all positive trials having used cisplatin.  Cisplatin use has subsequently increased though there is not a demonstrable improvement is survival associated with its use.  I also showed that survival overall, regardless of use of chemotherapy, has improved suggesting that the application of clinical trial data for adjuvant chemotherapy is improving outcome.  In a related study, I found that elderly patients benefit as much as younger patients from adjuvant chemotherapy.  Patients with stage III non-small cell lung cancer are frequently treated with concurrent chemoradiotherapy, for which there are two commonly used chemotherapy regimens: cisplatin-etoposide and carboplatin-paclitaxel.  I examined the outcome and toxicity of patients treated with these two regimens and found that while there was no significant difference in survival, there was more toxicity associated with cisplatin-etoposide.  This finding may impact one current clinical guideline recommendation that favors cisplatin-etoposide over carboplatin-paclitaxel.  Finally, in stage IV disease, a similar observation was made that cisplatin-based chemotherapy is associated with greater toxicity but not improved survival. 

Complete List of Published Work in MyBibliography:   http://www.ncbi.nlm.nih.gov/sites/myncbi/michael.kelley.1/bibliography/43511621/public/?sort=date&direction=descending

Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1985

University of Michigan, Ann Arbor

Medical Resident, Medicine

Duke University

Grants:

Measurement of Hypoxia in Non-Small Cell Lung Carcinoma

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Quit-smoking program for lung cancer patients' families

Administered By
Duke Cancer Institute
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Preference Tx for Sequencing in NSCLC

Administered By
Duke Clinical Research Institute
Awarded By
AstraZeneca Pharmaceuticals, LP
Role
Co Investigator
Start Date
End Date

IPA - Bradley Hintze

Administered By
Medicine, Medical Oncology
Awarded By
Durham Veterans Affairs Medical Center
Role
Principal Investigator
Start Date
End Date

Chordoma Foundation Brachyury Mouse Model Project

Administered By
Medicine, Medical Oncology
Awarded By
Chordoma Foundation
Role
Principal Investigator
Start Date
End Date

Publications:

Comparison of characteristics and outcomes among veterans receiving first-line immunotherapy versus chemotherapy for stage IV non-small cell lung cancer.

Authors
Williams, CD; Gu, L; Vashistha, V; Press, A; Kelley, MJ
MLA Citation
URI
https://scholars.duke.edu/individual/pub1475614
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
38
Published Date

TARGETING SMARCBi IN PEDIATRIC CHORDOMA DEVELOPMENT

Authors
Walhart, T; Weissman, B; Yip, S; Alcorta, D; Kelley, M
MLA Citation
Walhart, Tara, et al. “TARGETING SMARCBi IN PEDIATRIC CHORDOMA DEVELOPMENT.” Oncology Nursing Forum, vol. 48, no. 2, 2021, pp. 8–8.
URI
https://scholars.duke.edu/individual/pub1477285
Source
wos-lite
Published In
Oncology Nursing Forum
Volume
48
Published Date
Start Page
8
End Page
8

The Impact of Current Smoking Status at Initiation of Immune Checkpoint Inhibitor Therapy on Tumor Mutation Burden and Survival

Authors
Wu, JT; La, J; Han, S; Das, M; Glover, M; Scobie, M; Brophy, M; Do, N; Ahmed, S; Fillmore, N; Kelley, M
MLA Citation
Wu, J. T., et al. “The Impact of Current Smoking Status at Initiation of Immune Checkpoint Inhibitor Therapy on Tumor Mutation Burden and Survival.” Journal of Thoracic Oncology, vol. 17, no. 9, 2022, pp. S359–60.
URI
https://scholars.duke.edu/individual/pub1555408
Source
wos-lite
Published In
Journal of Thoracic Oncology
Volume
17
Published Date
Start Page
S359
End Page
S360

Clinical outcomes of immune checkpoint inhibitor (ICI) therapy among Veterans Affairs patients with colorectal cancer and discordant dMMR/MSI-H status.

Authors
Isaacs, J; Guo, A; Vashistha, V; Katsoulakis, E; Boswell, E; Strickler, JH; Ahmed, S; Kelley, MJ
URI
https://scholars.duke.edu/individual/pub1555488
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
40
Published Date

Adoption of Extended-Interval Dosing of Single-Agent Pembrolizumab and Comparative Effectiveness vs Standard Dosing in Time-to-Treatment Discontinuation.

IMPORTANCE: Extended-interval dosing of pembrolizumab (400 mg every 6 weeks) was approved by US Food and Drug Administration (FDA) in April 2020 as an alternative to standard-interval dosing (200 mg every 3 weeks). Extended-interval dosing may enhance access, alleviate patient and health system financial toxicity, and improve patient quality of life, particularly during the COVID-19 pandemic. Neither adoption nor effectiveness of extended interval in the US has been adequately described. OBJECTIVE: To describe adoption of extended-interval dosing of pembrolizumab since its FDA approval and to measure its preliminary real-world effectiveness compared with standard-interval dosing. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study that used data from the Veterans Health Administration (VHA), a US-based, nationwide single-payer health system. Participants were veterans who were prescribed single-agent pembrolizumab within the VHA between April 1, 2020, and July 1, 2021. Patients receiving combinations of pembrolizumab and cytotoxic chemotherapy or tyrosine kinase inhibitors were excluded. A subcohort of veterans with non-small cell lung cancer (NSCLC) was also identified using claims-based codes. EXPOSURES: Single-agent pembrolizumab at extended or standard intervals. MAIN OUTCOMES AND MEASURES: The number and proportion of single-agent pembrolizumab prescriptions that were extended compared with standard interval. Effectiveness was described in terms of time-to-treatment discontinuation (TTD) and extended- to standard-interval pembrolizumab prescriptions were compared using Cox proportional hazards regression. RESULTS: A total of 835 veterans (mean age [SD], 70.9 [8.7] years; 809 [96.9%] men) began single-agent pembrolizumab during the study period (all-diseases cohort), and of these, 234 (mean [SD] age, 71.6 [7.3] years; 225 [96.2%] men) had NSCLC (NSCLC cohort). Extended-interval adoption reached its steady state plateau of approximately 35% by January 2021; 65% of participants who began standard-interval single-agent pembrolizumab received only standard-interval dosing during the treatment course. In analysis consistent with the intention-to-treat principle, no differences in TTD were observed between standard- and extended-interval dosing in either the all-diseases cohort (HR, 1.00; 95% CI, 1.00-1.00) or the NSCLC cohort (HR, 1.00; 95% CI, 1.00-1.00). CONCLUSIONS AND RELEVANCE: This retrospective cohort study found that extended-interval dosing comprised a minority of single-agent pembrolizumab prescriptions despite the FDA approval and its potential health system and public health benefits. The findings support the TTD equivalence of standard- and extended-interval pembrolizumab across indications, complementing clinical pharmacology and single-arm clinical trial data in melanoma. This study provides further support for extended-interval pembrolizumab dosing.
Authors
Strohbehn, GW; Holleman, R; Burns, J; Klamerus, ML; Kelley, MJ; Kerr, EA; Ramnath, N; Hofer, TP
MLA Citation
Strohbehn, Garth W., et al. “Adoption of Extended-Interval Dosing of Single-Agent Pembrolizumab and Comparative Effectiveness vs Standard Dosing in Time-to-Treatment Discontinuation.Jama Oncol, vol. 8, no. 11, Nov. 2022, pp. 1663–67. Pubmed, doi:10.1001/jamaoncol.2022.4109.
URI
https://scholars.duke.edu/individual/pub1550869
PMID
36136314
Source
pubmed
Published In
Jama Oncol
Volume
8
Published Date
Start Page
1663
End Page
1667
DOI
10.1001/jamaoncol.2022.4109