Table 3 Drugs targeting the NOTCH signaling pathway assessed in clinical trials

GSI

PF-03084014

NCT00878189⁵⁶⁰

2009

I

Completed

Solid malignancies, N = 64

ORR: 13%;

1 CR observed in patients with advanced thyroid cancer, and 5 PRs in patients with desmoid tumors;

All-grade AEs: 84.4%, grade ≥ 3 AEs: 35.9%.

NCT00878189⁶⁶⁵

2009

I

Completed

T-ALL and T-LBL, N = 8

1 CR in a T-ALL patient with NOTCH1 mutation.

NCT02299635

2015

II

Terminated

TNBC, N = 19

SAEs: 6/19;

study terminated prematurely based on project reprioritization by the sponsor.

NCT01981551⁵⁷¹

2013

II

Active

Desmoid tumors (aggressive fibromatosis), N = 17

5 (29%) patients experienced a PR for more than 2 years with tolerable toxicity.

NCT04195399

2020

II

Recruiting

Progressive, surgically unresectable desmoid tumors, N = 35

-

RO4929097

NCT00532090⁵⁶¹

2007

I

Completed

Platinum-resistant ovarian cancer, N = 110

1 PR in patients with colorectal adenocarcinoma with neuroendocrine features;

1 nearly complete FDG-PET response in a patient with melanoma.

NCT01119599⁵⁶²

2010

0/I

Completed

Glioma, N = 21

No dose-limiting toxicities were observed in combination with temozolomide;

decreased expression of NICD in tumor cells and blood vessels.

NCT01175343⁵⁶⁹

2010

II

Completed

Platinum-resistant ovarian cancer, N = 45

No objective responses were observed.

NCT01122901⁶⁶⁶

2010

II

Completed

GBM, N = 47

Inactive in recurrent GBM patients.

NCT01120275⁵⁶⁸

2016

II

Completed

Metastatic melanoma, n = 32

Tolerated but did not achieve NOTCH target inhibition.

NCT01116687⁵⁷⁰

2010

II

Completed

Metastatic colorectal cancer, N = 37

No radiographic responses were seen, and time to progression was short.

MK-0752

NCT00100152

2005

I

Terminated

T-ALL, N = 50

1/6 patients showed 45% reduction in mediastinal mass;

study was halted for severe diarrhea.

NCT00106145⁶⁶⁷

2005

I

Completed

Solid tumors, N = 103

1 objective response and 10 cases of SD were observed in patients with high-grade gliomas;

weekly dosing was generally well tolerated.

NCT00572182⁵⁶⁶

2008

I

Terminated

Brain and central nervous system tumors, N = 33

No objective responses were reported in 23 pediatric patients;

study terminated by sponsor.

NCT00645333⁶⁶⁸

2008

I/II

Completed

Breast cancer, N = 30

Enhanced the efficacy of docetaxel with manageable toxicity.

NCT00756717

2008

IV

Completed

Breast cancer, N = 20

No serious adverse events;

No available efficacy data..

LY3039478

NCT01695005^565,669,670

2012

I

Completed

Solid cancers, N = 237

Prednisone might reduce gastrointestinal toxicities;

PR was observed in 1 patient with breast cancer, 1 patient with leiomyosarcoma and 1 patient with angiosarcoma.

NCT02518113⁶⁷¹

2015

I

Completed

T- ALL/T-LBL, N = 36

6 patients (16.7%) experienced DLTs;

1 patient (2.8%) had a confirmed response that lasted 10.51 months.

NCT02784795⁶⁷²

2016

Ib

Completed

Solid cancer, N = 94

Combination with other anticancer agents produced disappointing results.

LY900009

NCT01158404⁵⁶⁴

2010

I

Completed

Solid cancer, N = 35

No objective response;

5/35 patients had a SD.

AL101

NCT04461600

2020

II

recruiting

NOTCH-activated TNBC, N = 67

-

NCT04973683

2021

I

recruiting

NOTCH-activated ACC, N = 12

-

DLL3

Rovalpituzumab tesirine (Rova-T)

NCT01901653⁶⁷³

2013

I

Completed

SCLC, N = 74

11 (18%) patients had an objective response, ten of whom had high DLL3 expression;

28 (38%) suffered serious drug-related adverse events.

NCT02819999⁵⁷⁹

2016

I

Terminated

SCLC, N = 26

There was no clear efficacy benefit of combining Rova-T with platinum-based chemotherapy.

NCT03026166⁵⁸⁹

2017

I/II

Terminated

SCLC, N = 42

ORR was 30% in patients treated with combination therapy with Rova-T and ICIs; however, the toxicity was high, suggesting that the combination was not well tolerated;

enrollment was stopped because of the DLT.

NCT02674568⁵⁸⁶

2016

II

Completed

SCLC, N = 339

Median OS was 5.6 months;

grade 3-5 AEs were seen in 213 (63%) patients;

Demonstrated modest clinical activity in 3L+ SCLC, with associated toxicities.

NCT03033511⁵⁸⁷

2017

III

Terminated

SCLC, N = 748

Lack of survival benefit of maintenance therapy with rovalpituzumab tesirine after first-line platinum-based chemotherapy;

the study did not meet its primary end point and was terminated early.

NCT03061812⁵⁸⁸

2017

III

Completed

SCLC, N = 444

Compared with topotecan, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reactions, and peripheral edema.

SC-002

NCT02500914⁵⁹¹

2015

I

Terminated

SCLC, N = 35

5 (14%) patients achieved a PR;

37% of patients had serious AEs considered to be related to SC-002;

no further development is planned because of the systemic toxicity and limited efficacy.

AM757

NCT03319940

2017

I

Recruiting

SCLC, N = 332

-

HPN328

NCT04471727

2020

I

Recruiting

SCLC, N = 67

-

DLL4

Enoticumab (REGN421)

NCT00187159⁵⁹⁴

2015

I

Completed

Solid tumors, N = 53

2 PRs were observed in patients with NSCLC and ovarian cancer;

MTD was not reached.

Demcizumab (OMP-21M18)

NCT00744563⁵⁹⁵

2014

I

Completed

Solid tumors, N = 55

Demonstrated antitumor activity with a low dose.

NCT01189968⁶⁷⁴

2010

I

Completed

Metastatic nonsquamous NSCLC, N = 40

Modulated the expression of genes regulating NOTCH signaling and angiogenesis;

increased the risk of cardiovascular disease when combined with pemetrexed and carboplatin.

NCT01952249⁵⁹⁶

2013

Ib/II

Phase Ib, completed; phase II, terminated

Platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer, N = 19

Researchers are no longer pursuing ovarian cancer as an indication;

the phase II portion of the study was terminated.

NOTCH1

Brontictuzumab (OMP-52M51)

NCT01778439⁴²⁰

2013

I

Completed

Selected refractory solid tumors, N = 48

2 patients achieved PR and 4 patients achieved ≥ 6 months of SD in ACC with NOTCH1 activation;

DLTs included diarrhea and fatigue.

NOTCH2/3

Tarextumab (OMP-59R5)

NCT01277146⁶¹⁶

2011

I

Completed

Solid tumors, N = 42

9 subjects had SD;

Lower doses were tolerated.

NCT01647828⁶¹⁵

2012

II

Completed

Untreated metastatic pancreatic cancer, N = 177

There were no OS, PFS, or ORR benefits with the addition of tarextumab to nab-paclitaxel and gemcitabine in first-line metastatic PDAC.

NCT01859741

2019

I/II

Terminated

SCLC, N = 172

Terminated for unimproved PFS in combination with etoposide and platinum therapy.

NOTCH3

PF-06650808

NCT02129205⁶¹⁷

2014

I

Terminated

Breast cancer and other advanced solid tumors, N = 40

5 PRs were observed with manageable safety;

all of responders had positive NOTCH3 expression;

the study was terminated due to a change in sponsor prioritization.