Niharika Mettu

Overview:

My long-term goal is to develop new therapies to treat patients with gastrointestinal and other solid tumors. To accomplish this, I am active in designing, writing, and running phase I and II clinical trials. I am also interested in the correlative science that furthers our understanding of cancer at a molecular level. I am interested in the identification of biomarkers, which are characteristics of a given patient's tumor that may help us to understand his or her prognosis or how well he or she may respond to a given therapy. The overall objective of this research is to use the knowledge gained to personalize care and find the very best therapies that will enable our patients to fight their cancer.

Positions:

Assistant Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2007

Duke University

M.D. 2008

Duke University School of Medicine

Internal Medicine Residency, Medicine

Duke University School of Medicine

Hematology-Oncology Fellowship, Medicine

Duke University School of Medicine

Grants:

A Randomized, Open-Label, Phase 2 Study of Nivolumab in Combination with Ipilimumab or Nivolumab Monotherapy in Participants with Advanced or Metastatic Solid Tumors of High Tumor Mutational Burden (TMB-H)

Administered By
Duke Cancer Institute
Awarded By
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
End Date

A Phase 1b/2 Study to Evaluate the Safety, Pharmacokinetics, and Clinical Activity of Oleclumab (MEDI9447) with or without Durvalumab in Combination with Chemotherapy in Subjects with Metastatic Pancreatic Ductal Adenocarcinoma

Administered By
Duke Cancer Institute
Awarded By
AstraZeneca LP
Role
Principal Investigator
Start Date
End Date

A Phase 1/2 study of exploring the safety tolerablility and efficacy of Epacadostat in combination with Durvalumab in subjects with selected advanced solid tumors.

Administered By
Duke Cancer Institute
Awarded By
Incyte Corporation
Role
Principal Investigator
Start Date
End Date

A platform study exploring the safety tolerability effects on the tumor microenvironment and efficacy of Pembroliumab (MK-3475) + INCB combination

Administered By
Duke Cancer Institute
Awarded By
Incyte Corporation
Role
Principal Investigator
Start Date
End Date

A Phase I open label dose escalation safety and tolerability study of INCB054828 in subjects with advanced malignancies

Administered By
Duke Cancer Institute
Awarded By
Incyte Corporation
Role
Principal Investigator
Start Date
End Date

Publications:

Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRASG12R-mutant pancreatic ductal adenocarcinoma.

Background Preclinical evidence has suggested that a subset of pancreatic cancers with the G12R mutational isoform of the KRAS oncogene is more sensitive to MAPK pathway blockade than pancreatic tumors with other KRAS isoforms. We conducted a biomarker-driven trial of selumetinib (KOSELUGO™; ARRY-142886), an orally active, allosteric mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor, in pancreas cancer patients with somatic KRASG12R mutations. Methods In this two-stage, phase II study (NCT03040986) patients with advanced pancreas cancer harboring somatic KRASG12R variants who had received at least one standard-of-care systemic therapy regimen received 75 mg selumetinib orally twice a day until disease progression or unacceptable toxicity occurred. The primary outcome of the study was best objective response (BOR). Results From August 2017 to February 2018 a total of 8 patients with confirmed somatic KRASG12R mutations and a median age of 61.5 years were treated with selumetinib. Seven out of eight (87.5%) had received two or more lines of prior systemic chemotherapy. After a median follow-up period of 8.5 months (range 2 to 20), three patients had stable disease for more than 6 months while receiving selumetinib. No patients achieved an objective partial response. Median progression-free survival (PFS) was 3.0 months (95% CI, 0.8-8.2) and median overall survival (OS) 9 months (95% CI, 2.5-20.9). Conclusion This study in heavily pre-treated pancreatic adenocarcinoma patients suggests alternative strategies beyond single agent MEK inhibition are required for this unique, molecular subset of pancreatic cancer patients. The trial was registered on February 2nd, 2017 under identifier NCT03040986 with ClinicalTrials.gov .
Authors
Kenney, C; Kunst, T; Webb, S; Christina, D; Arrowood, C; Steinberg, SM; Mettu, NB; Kim, EJ; Rudloff, U
MLA Citation
Kenney, Cara, et al. “Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRASG12R-mutant pancreatic ductal adenocarcinoma.Invest New Drugs, vol. 39, no. 3, June 2021, pp. 821–28. Pubmed, doi:10.1007/s10637-020-01044-8.
URI
https://scholars.duke.edu/individual/pub1470866
PMID
33405090
Source
pubmed
Published In
Invest New Drugs
Volume
39
Published Date
Start Page
821
End Page
828
DOI
10.1007/s10637-020-01044-8

Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer.

BACKGROUND: The immunosuppressive desmoplastic stroma of pancreatic cancer represents a major hurdle to developing an effective immune response. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine kinase (BTK) inhibition combined with programmed cell death receptor-1 (PD-1) blockade. METHODS: This was a phase II, multicenter, open-label, randomized (1:1) clinical trial evaluating the BTK inhibitor acalabrutinib, alone (monotherapy) or in combination with the anti-PD-1 antibody pembrolizumab (combination therapy). Eligible patients were adults with histologically confirmed metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1 who had received at least one prior systemic therapy. Oral acalabrutinib 100 mg twice daily was administered with or without intravenous pembrolizumab 200 mg on day 1 of each 3-week cycle. Peripheral blood was analyzed for changes in immune markers, and tumors from exceptional responders were molecularly analyzed. RESULTS: A total of 77 patients were enrolled (37 monotherapy; 40 combination therapy) with a median age of 64 years; 77% had an ECOG PS of 1. The median number of prior therapies was 3 (range 1-6). Grade 3-4 treatment-related adverse events were seen in 14.3% of patients in the monotherapy arm and 15.8% of those in the combination therapy arm. The overall response rate and disease control rate were 0% and 14.3% with monotherapy and 7.9% and 21.1% with combination therapy, respectively. Median progression-free survival was 1.4 months in both arms. Peripheral blood flow analysis demonstrated consistent reductions in granulocytic (CD15+) myeloid-derived suppressor cells (MDSCs) over time. Two exceptional responders were found to be microsatellite stable with low tumor mutation burden, low neoantigen load and no defects in the homologous DNA repair pathway. CONCLUSIONS: The combination of acalabrutinib and pembrolizumab was well tolerated, but limited clinical activity was seen with either acalabrutinib monotherapy or combination therapy. Peripheral reductions in MDSCs were seen. Efforts to understand and target the pancreatic tumor microenvironment should continue. TRIAL REGISTRATION NUMBER: NCT02362048.
Authors
Overman, M; Javle, M; Davis, RE; Vats, P; Kumar-Sinha, C; Xiao, L; Mettu, NB; Parra, ER; Benson, AB; Lopez, CD; Munugalavadla, V; Patel, P; Tao, L; Neelapu, S; Maitra, A
MLA Citation
Overman, Michael, et al. “Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer.J Immunother Cancer, vol. 8, no. 1, Feb. 2020. Pubmed, doi:10.1136/jitc-2020-000587.
URI
https://scholars.duke.edu/individual/pub1434704
PMID
32114502
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
8
Published Date
DOI
10.1136/jitc-2020-000587

Clinical Insights Into the Biology and Treatment of Pancreatic Cancer.

Pancreatic cancer is a devastating disease with a universally poor prognosis. In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer and that 40,560 people will die of the disease. The 5-year survival rate is 7.2% for all patients with pancreatic cancer; however, survival depends greatly on the stage at diagnosis. Unfortunately, 53% of patients already have metastatic disease at diagnosis, which corresponds to a 5-year survival rate of 2.4%. Even for the 9% of patients with localized disease confined to the pancreas, the 5-year survival is still modest at only 27.1%. These grim statistics highlight the need for ways to identify cohorts of individuals at highest risk, methods to screen those at highest risk to identify preinvasive pathologic precursors, and development of effective systemic therapies. Recent clinical and translational progress has emphasized the relationship with diabetes, the role of the stroma, and the interplay of each of these with inflammation in the pathobiology of pancreatic cancer. In this article, we will discuss these relationships and how they might translate into novel management strategies for the treatment of this disease.
MLA Citation
Mettu, Niharika B., and James L. Abbruzzese. “Clinical Insights Into the Biology and Treatment of Pancreatic Cancer.J Oncol Pract, vol. 12, no. 1, Jan. 2016, pp. 17–23. Pubmed, doi:10.1200/JOP.2015.009092.
URI
https://scholars.duke.edu/individual/pub1118899
PMID
26759461
Source
pubmed
Published In
J Oncol Pract
Volume
12
Published Date
Start Page
17
End Page
23
DOI
10.1200/JOP.2015.009092

Use of molecular biomarkers to inform adjuvant therapy for colon cancer.

The decision about who may derive benefit from adjuvant chemotherapy in colon cancer is often a difficult one for clinicians. While multiple trials have demonstrated that adjuvant chemotherapy reduces the risk of recurrence and improves overall survival in patients with stage III disease, the data supporting the use of adjuvant chemotherapy in patients with stage II disease are not as compelling. Because adjuvant therapy can have significant toxicity, tools to help clinicians determine who may derive a benefit from therapy are of the utmost importance. Recent advances in high throughput technologies have led to the identification of molecular biomarkers-including microsatellite instability (MSI), loss of heterozygosity (LOH), p53, Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), thymidylate synthase (TS), and excision repair cross-complementation group 1 (ERCC1)--as well as various multigene assays that are being studied for their ability to offer both prognostic and predictive information to clinicians. Here we review the current knowledge about molecular biomarkers that may aid the clinician in offering personalized cancer therapy based on the genetic landscape of an individual patient's tumor.
Authors
Mettu, NB; Hurwitz, H; Hsu, DS
MLA Citation
Mettu, Niharika B., et al. “Use of molecular biomarkers to inform adjuvant therapy for colon cancer.Oncology (Williston Park), vol. 27, no. 8, Aug. 2013, pp. 746–54.
URI
https://scholars.duke.edu/individual/pub1165753
PMID
24133820
Source
pubmed
Published In
Oncology (Williston Park, N.Y.)
Volume
27
Published Date
Start Page
746
End Page
754

Use of molecular biomarkers to inform adjuvant therapy for colon cancer

The decision about who may derive benefit from adjuvant chemotherapy in colon cancer is often a difficult one for clinicians. While multiple trials have demonstrated that adjuvant chemotherapy reduces the risk of recurrence and improves overall survival in patients with stage III disease, the data supporting the use of adjuvant chemotherapy in patients with stage II disease are not as compelling. Because adjuvant therapy can have significant toxicity, tools to help clinicians determine who may derive a benefit from therapy are of the utmost importance. Recent advances in high throughput technologies have led to the identification of molecular biomarkers-including microsatellite instability (MSI), loss of heterozygosity (LOH), p53, Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), thymidylate synthase (TS), and excision repair cross-complementation group 1 (ERCC1)-as well as various multigene assays that are being studied for their ability to offer both prognostic and predictive information to clinicians. Here we review the current knowledge about molecular biomarkers that may aid the clinician in offering personalized cancer therapy based on the genetic landscape of an individual patient's tumor.
Authors
Mettu, NB; Hurwitz, H; Hsu, DS
MLA Citation
Mettu, N. B., et al. “Use of molecular biomarkers to inform adjuvant therapy for colon cancer.” Oncology (United States), vol. 27, no. 8, Jan. 2013.
URI
https://scholars.duke.edu/individual/pub962151
Source
scopus
Published In
Oncology (Williston Park, N.Y.)
Volume
27
Published Date